Next Article in Journal
Effect of Solar Radiation on Skin Microbiome: Study of Two Populations
Next Article in Special Issue
Hepatitis E Virus Detection in Hunted Wild Boar Liver and Muscle Tissues in Central Italy
Previous Article in Journal
First Cases of Candida auris in a Referral Intensive Care Unit in Piedmont Region, Italy
Previous Article in Special Issue
CAMPYAIR, a New Selective, Differential Medium for Campylobacter spp. Isolation without the Need for Microaerobic Atmosphere
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Listeria monocytogenes Pathogenesis: The Role of Stress Adaptation

Department of Consumer and Food Sciences, University of Pretoria, Private Bag X20, Hatfield, Pretoria 0028, South Africa
Department of Applied Biology and Biochemistry, National University of Science and Technology, Bulawayo P.O. Box AC939, Zimbabwe
Author to whom correspondence should be addressed.
Microorganisms 2022, 10(8), 1522;
Submission received: 31 May 2022 / Revised: 8 July 2022 / Accepted: 19 July 2022 / Published: 27 July 2022
(This article belongs to the Special Issue Foodborne Pathogens: Infections and Pathogenesis)


Adaptive stress tolerance responses are the driving force behind the survival ability of Listeria monocytogenes in different environmental niches, within foods, and ultimately, the ability to cause human infections. Although the bacterial stress adaptive responses are primarily a necessity for survival in foods and the environment, some aspects of the stress responses are linked to bacterial pathogenesis. Food stress-induced adaptive tolerance responses to acid and osmotic stresses can protect the pathogen against similar stresses in the gastrointestinal tract (GIT) and, thus, directly aid its virulence potential. Moreover, once in the GIT, the reprogramming of gene expression from the stress survival-related genes to virulence-related genes allows L. monocytogenes to switch from an avirulent to a virulent state. This transition is controlled by two overlapping and interlinked transcriptional networks for general stress response (regulated by Sigma factor B, (SigB)) and virulence (regulated by the positive regulatory factor A (PrfA)). This review explores the current knowledge on the molecular basis of the connection between stress tolerance responses and the pathogenesis of L. monocytogenes. The review gives a detailed background on the currently known mechanisms of pathogenesis and stress adaptation. Furthermore, the paper looks at the current literature and theories on the overlaps and connections between the regulatory networks for SigB and PrfA.

1. Introduction

Listeria monocytogenes is a foodborne pathogen that is the causative agent of the human disease, listeriosis. It is primarily a ubiquitous environmental saprophyte found in many environmental niches such as water, soil, and vegetation [1]. Contaminated, often ready-to-eat (RTE) foods are the main transmission vehicles for human L. monocytogenes infections [2,3,4]. In most individuals, L. monocytogenes infections frequently result in mild, self-limiting febrile gastroenteritis [5]. However, in susceptible individuals, such as infants, the elderly, pregnant women and people who are immunocompromised, infections result in invasive listeriosis which has a high fatality rate of 20–30% [5]. As an invasive intracellular pathogen, L. monocytogenes depends on an arsenal of adhesion and invasion factors that facilitate its gastrointestinal tract (GIT) colonization and transit through the intestinal barrier [6]. Additionally, other virulence factors such as the cytolysin (listeriolysin O), actin polymerization protein ActA and phospholipases are important for the pathogen’s intracellular survival and spread of infection [7,8,9].
As a foodborne pathogen, L. monocytogenes encounters several physical and chemical stresses that impede its growth and survival along the food value chain [10]. In response to stress exposures, foodborne pathogens develop mechanisms to adjust cellular processes to a state that allows them to maintain viability and growth under stressful conditions [11]. The development of stress adaptive responses is a process that results from the sensing of environmental changes and reprogramming of gene expression towards the synthesis of stress response proteins that aid bacterial survival under harsh conditions [12]. This stress adaptation is the driving force behind the ability of L. monocytogenes to colonize and survive in different niches within food processing environments and to survive food processing and preservation hurdles [13].
In addition to bacterial stress adaptation being a necessity for survival in foods and the environment, some aspects of the stress responses are linked to bacterial pathogenesis [14]. Being an orally transmitted pathogen, L. monocytogenes must overcome the hostile host-defence systems in the human GIT as a first step to establishing a successful infection [14]. Some of these in vivo stress conditions such as acidic pH, increased osmolarity, and oxidative stress are conditions also encountered by the organism in foods and the environment [15]. Hence, food stress-induced adaptive tolerance responses to acid, osmotic and oxidative stresses can protect the pathogen against similar stresses in the GIT, and thus, directly aid its pathogenicity potential [16]. For some time, it has been known that the general stress response regulator (Sigma factor B, (SigB)) that controls the expression of genes for L. monocytogenes environmental stress adaptation, also controls the expression of some virulence factors involved in GIT colonization and pathogen internalization by the intestinal epithelium [17,18]. Besides the overlapping function of SigB, evidence has shown that the relationship between stress responses and virulence are intricately connected through direct and indirect interactions between the stress response regulator and the virulence regulator (positive regulatory factor A, (PrfA)) [19,20,21]. This review explores the current knowledge on the molecular basis of the connection between stress tolerance responses and the pathogenesis of L. monocytogenes. The review gives a detailed background on the currently known mechanisms of L. monocytogenes pathogenesis and the mechanisms of stress adaptation. Furthermore, the paper looks at the current theories and models explaining the connections between the stress response and virulence regulatory networks.

2. Overview of L. monocytogenes Infection Cycle

Through the ingestion of contaminated food, L. monocytogenes enters the GIT, where it can traverse the small intestines and establish a systemic infection that disseminates the pathogen to its main target organs (Figure 1). In most healthy individuals, L. monocytogenes infections remain largely extracellular within the intestinal lumen and often manifest with intestinal symptoms, typically as febrile gastroenteritis [6]. However, in susceptible individuals, the organism invades the epithelial barrier and crosses into the underlying lamina propria and mesenteric lymph nodes [22]. The organism is subsequently carried in the blood to the liver and spleen through the portal circulation [23]. In the liver and spleen, L. monocytogenes is first taken up by Kupffer cells and splenic dendritic cells as resident phagocytes in the respective organs [24,25]. Initially, the bacterial cells are contained within a membrane-bound vacuole inside the phagocytic cells. The bacteria subsequently lyse the vacuole and replicate within the cytosol of infected phagocytes before spreading into neighboring parenchymal cells [23]. In about 2–3 days following the initial phase of invasion, the bacterial multiplication inside the liver reaches maximum growth [23]. The susceptibility of the liver and spleen as the initial target organs for L. monocytogenes colonization and replication is thought to be a result of the fenestrated hepatic and splenic capillaries that permit an easy diffusion of L. monocytogenes from the bloodstream [23]. As replication niches, the liver and spleen act as reservoirs for L. monocytogenes, thus, enabling a re-seeding of the pathogen into the bloodstream, leading to the infection of additional organs [23]. In addition to establishing a systemic infection, studies in experimentally infected mice have shown that the organism can establish long-term colonization of the cecum and lumen of the colon, thus, creating a reservoir for the faecal spread of the organism back to the environment [26].

3. Pathogenesis of Invasive L. monocytogenes Infections

3.1. L. monocytogenes Virulence Factors

L. monocytogenes expresses several surface and soluble proteins that mediate the adhesion to target cells, internalization, intracellular multiplication and dissemination to other host cells [6]. The virulence factors are encoded either as separate loci across the bacterial genome or as clusters on pathogenicity islands [27]. A core of virulence genes (prfA, hly, actA, plcA, mpl, and plcB) encoded on the Listeria pathogenicity island 1 (LIPI-1) is conserved in the genomes of all L. monocytogenes strains [27]. Additionally, many other virulence factors encoded in separate loci, such as the internalin A/Internalin B (inlAB) operon, are also part of the virulence arsenal conserved in all L. monocytogenes strains [28]. The characteristics and roles of some of these proteins in the pathogenesis of L. monocytogenes are discussed in this section.
Listeria adhesion protein (LAP). LAP is a 104-kDa cell wall protein ubiquitously found in all Listeria species [29]. It was first described by Pandiripally et al. [30] as protein p104 which was subsequently found to be an alcohol acetaldehyde dehydrogenase [31]. As an essential enzyme, LAP is produced primarily as a cytosolic protein in all Listeria species. However, in pathogenic species, the protein is translocated to the cell surface through the SecA2 secretory system to facilitate the adhesion of pathogenic Listeria species to intestinal cells [32,33]. The epithelial receptor for LAP is a constitutively expressed mitochondrial protein, heat shock protein 60 (Hsp60) [29]. In addition to acting as an adhesin, LAP has also been implicated in the translocation of the pathogen across the intestinal epithelium [34].
Fibronectin binding protein (FbpA). Fibronectin binding proteins (Fbp) are cell wall-anchored proteins that are widely distributed in Gram-positive bacteria [35]. Fbps recognize and bind to fibronectin (a component of the human extracellular matrix that plays a role in inter-cellular interaction and adhesion) [36]. The interaction between bacterial Fbps and fibronectin molecules forms a three-component bridge (involving integrins), which facilitates the adhesion between the bacterial and the host cells [35]. The Fbp of L. monocytogenes (FbpA) was characterized by Dramsi et al. [37]. It is a 570-amino-acid polypeptide that shares a high homology to streptococcal Fbps (PavA of Streptococcus. pneumoniae, Fbp54 of S. pyogenes and FbpA of S. gordonii) [37]. However, unlike streptococcal Fbps, the L. monocytogenes FbpA is exposed on the surface of the bacterial cell without the signal peptide [37].
Internalin A (InlA). InlA is one of the principal virulence factors of L. monocytogenes that was first described by Gaillard et al. [38]. It is an 80 kDa protein that is anchored onto the cell wall peptidoglycan through a C-terminal LPXTG motif [39]. InlA mediates the adhesion and internalization of the pathogen into enterocytes in the first step of invasion of the intestinal barrier [22]. An N-terminal leucine-rich repeat (LRR) domain acts as the recognition and binding site to the EC1 domain of the extracellular portion of E-cadherin [40,41].
Internalin B (InlB). InlB is another adhesion protein that plays a major role in L. monocytogenes binding to enterocytes and the subsequent invasion of the intestinal barrier [39]. Unlike InlA, InlB is anchored onto the cell wall through glycine and tryptophan (GW) modules that non-covalently interact with cell wall teichoic acids [42]. The LRR domain acts as the recognition and binding site to Met (a host receptor tyrosine kinase) [22]. L. monocytogenes also produces many other LRR proteins classified under the internalin family [43]. However, InlA and InlB have been identified as the principal adhesion proteins that mediate pathogen binding and invasion [44].
Listeriolysin O (LLO). LLO is a 56 kDa pore-forming cytotoxin encoded by the hly gene [45,46]. It belongs to the family of cholesterol-dependent cytolysins (CDCs) [46]. It was one of the first L. monocytogenes virulence factors identified, based on the ability of virulent strains to cause hemolysis on blood agar [47]. Subsequent experiments identified the hemolysin as a sulfhydryl-activated toxin responsible for the intracellular growth of L. monocytogenes in human enterocyte-like Caco-2 cells [48,49]. The role of LLO is the lysis of the internalization vacuole, resulting in the release of the pathogen into the cytosol of host cells [50].
Phospholipases. Two types of phospholipases are required for L. monocytogenes. Phosphatidylinositol-specific phospholipase C (PI-PLC) is encoded by the plcA gene while phosphatidylcholine phospholipase C (PC-PLC) is encoded by the plcB gene [51,52]. PI-PLC plays a complementary role together with LLO in the lysis of the primary and secondary vacuole following pathogen internalization [44]. It catalyzes the cleavage of the membrane phosphatidylinositol into inositol phosphate and diacylglycerol [53]. PC-PLC is a broad-range phospholipase which is particularly required for the lysis of the double-membrane secondary vacuole and the primary vacuole in conditions of LLO deficiency [54]. PC-PLC is synthesized as a 33-kDa precursor that requires cleavage to produce the active 29-kDa enzyme [55]. A zinc-dependent metalloprotease (Mpl) encoded by the mpl gene is required for the maturation of PC-PLC [55].
Actin-polymerizing protein ActA. ActA is a surface protein encoded by the actA gene [56]. It mediates bacterial motility inside infected host cells through actin polymerization [56]. The protein is anchored on the bacterial cell membrane through its hydrophobic C-terminal domain while the functional N-terminal domain is exposed to the host cell cytoplasm [56]. Within the bacterial cell surface, ActA exhibits an asymmetrical distribution, being more concentrated at one polar end of the cell. The asymmetrical distribution is responsible for the directionality of L. monocytogenes motility [57,58]. To facilitate intracellular motility, ActA mediates actin nucleation and filament formation through the recruitment of host vasodilator-stimulated phosphoprotein (VASP) and actin-related proteins-2 and 3 (Arp2/3) complex [59,60].

3.2. Gastrointestinal Tract Colonization and Invasion of Host Cells

Due to its severity and high fatality rates, much of the focus on the pathogenesis of listeriosis is placed on invasive infections. However, evidence shows that non-invasive listerial febrile gastroenteritis outbreaks are very common [61,62,63,64]. Non-invasive L. monocytogenes infections are typically characterized by enteric symptoms such as vomiting, non-bloody diarrhea, nausea and fever that occur within a short period (24 h) following the ingestion of contaminated foods [62,65]. The mechanisms underlying the pathogenesis of non-invasive L. monocytogenes infections remain unclear [65]. Recently, a few studies have attempted to elucidate the mechanisms of L. monocytogenes gastrointestinal tract colonization [26,65]. Based on in vitro and mice models, the actin polymerization protein ActA—which mediates the cell-to-cell spread of the pathogen in invasive listeriosis—has also been implicated in intestinal colonization [26]. Using actA gene mutants in orally infected mice, Travier et al. [26] found that ActA can mediate L. monocytogenes aggregation both in vitro and in the gut lumen. The postulated mechanism of the ActA-mediated aggregation is based on direct ActA–ActA interactions through the C-terminal regions (which are not involved in polymerization) [26]. In the same study, the researchers found that ActA-dependent aggregation was also responsible for an increased ability to persist within the cecum and colon lumen of mice. Additionally, Halbedel et al. [65] observed a genetic correlation between the L. monocytogenes disease outcome (invasive or non-invasive) and the presence or absence of a functional chitinase gene (chiB) in which gastroenteritis outbreak isolates possessed a premature stop codon in the chiB gene. However, the restoration of chitinase production in a non-invasive isolate could not generate the invasiveness characteristic [65].
The first step in the pathogenesis of invasive listeriosis is the ability of the pathogen to cross the intestinal epithelial barrier. Although the complete mechanisms are still not fully understood, three well-elucidated pathways have thus far been used to explain the process [22]. These three pathways (Figure 2) are the InlA-mediated transcytosis, the LAP-mediated translocation, and the microfold (M-cell)-mediated transcytosis [22].
InlA-mediated transcytosis. The InlA- mediated pathway (Figure 2) is the primary route by which L. monocytogenes invades intestinal cells. InlA is a cell wall-anchored protein that mediates the uptake of L. monocytogenes into non-phagocytic cells through receptor-mediated endocytosis [66]. InlA promotes pathogen adhesion and the invasion of the intestinal epithelium through an interaction with its receptor, E-cadherin (a component of adherens junctions) [44]. Adherens junctions, tight junctions, and desmosomes are part of the apical junctional complex that provides a paracellular seal between adjacent epithelial cells [22]. The InlA interaction with receptors occurs at sites where E-cadherin is transiently exposed to the intestinal lumen [67,68]. The transient exposure of E-cadherin occurs during cell extrusion and junction remodeling [68]. Furthermore, changes in the shape of goblet cells can also result in the exposure of the E-cadherin component of the cell junctions [67]. Through interaction with the receptor, bacterial cells are taken into the enterocytes by endocytosis and are subsequently then released into the lamina propria by exocytosis [22]. The binding of InlA induces the recruitment of other junctional proteins, α-catenin and β-catenin, as well as actin and p120 catenin, which facilitate E-cadherin clustering at the site of bacterial entry [69]. Subsequently, a post-translational modification of E-cadherin (phosphorylation by the tyrosine kinase, Src and ubiquitination by the ubiquitin-ligase Hakai) induces endocytosis through caveolin or clathrin [22,69]. Ultimately, the InlA/E-cadherin-mediated endocytosis involves components of the host cytoskeleton that facilitate the formation of localized host cell membrane protrusions that force the formation of endocytic vesicles around the adherent bacteria cell [44]. It is now known that host cytoskeletal proteins involved in actin nucleation such as the Arp2/3 complex and VASP are activated in response to InlA binding to its receptors [39,70].
Unlike InlA, InlB does not play a major role in the invasion of intestinal cells [39]. However, together with InlA, it plays a role in the invasion of other tissues such as the liver, spleen, CNS and placenta [23]. The InlB receptor is the ubiquitous tyrosine kinase Met whose normal ligand is Hepatocyte Growth Factor (HGF) [44]. The binding of InlB to Met results in the autophosphorylation of the cytoplasmic tail of the Met proteins, initiating a reaction cascade that culminates in the localized polymerization of actin and internalization of bacterial cells in the same way as InlA [66].
LAP-mediated translocation. For a long time, the InlA-mediated pathway was established as the main route of L. monocytogenes traversal of the intestinal epithelium [67,68,69]. However, subsequent evidence that strains possessing non-functional InlA could cause infections in orally dosed mice and guinea pigs [71,72] showed that the pathogen can use alternative mechanisms to achieve intestinal invasion [34]. The surface protein, LAP, which was initially identified as an adhesin that facilitates the binding of L. monocytogenes to enterocytes, also contributes to the translocation of the pathogen across the intestinal epithelium [34]. The pathway of LAP-mediated invasion (Figure 2) was elucidated by Drolia et al. [34] using a Caco-2 cell line and a mouse model. The researchers showed that LAP induces the intestinal epithelial barrier dysfunction as a mechanism of promoting bacterial translocation. The binding of LAP to its luminal receptor protein Hsp60 activates myosin light-chain kinase (MLCK) that mediates the opening of the intestinal barrier through the redistribution of junctional proteins, claudin-1, occludin, and E-cadherin [34]. These reactions cause the opening of tight junctions between neighboring enterocytes allowing L. monocytogenes translocation [22,34]. Furthermore, the LAP-mediated translocation is thought to be an important precursor event for the InlA-dependent invasion, as it potentially provides pathogen access to E-cadherin in exposed adherens junctions [34].
M-cell mediated transcytosis. The microfold (M) cells are specialized epithelial cells that survey the intestinal mucosa for any antigens as part of the mucosal immune response. They readily take up antigens from the intestinal mucosa and transcytose them across the intestinal epithelium to the lymphoid tissues of the Peyer’s patches [73]. This process also serves as a passive route for the transcytosis of pathogens into the basolateral side of the follicle-associated epithelium [74]. While the role of M-cells in the transcytosis of L. monocytogenes has been well established, the mechanism of the pathogen interaction with such cells is not fully understood [74]. Evidence from in vitro and orally infected mice models has shown that in the absence of InlA, L. monocytogenes rapidly accumulate in the Peyer’s patches [75,76]. The prevailing paradigm on the M-cell mediated pathway is that transcytosis occurs across the M cells through a vacuole [22,23]. However, Rey et al. [74] established that in addition to the rapid vacuolar transcytosis, L. monocytogenes also escapes to the cytosol of the M-cells by vacuolar rupture. Once in the M-cell cytosol, the pathogen can initiate a direct ActA-based M-cell-to-enterocyte spread [74].

3.3. Intracellular Survival and Dissemination

The ability to cross the intestinal barrier provides the main gate of L. monocytogenes entry into the bloodstream. Due to its predilection for the CNS and the placenta in pregnant women, neurolisteriosis, maternofetal infection and septicemia are the main clinical manifestations of invasive listeriosis [77]. The high tropism of L. monocytogenes for these tissues is unclear. The possible explanation has been attributed to the presence of E-cadherin and Met, the two receptor proteins for InlA and InlB, respectively [7]. Because of the presence of Met in the human umbilical vein endothelial cells (HUVEC), L. monocytogenes can invade the human placenta through an InlB-dependent mechanism [78]. In the CNS, both receptors are expressed at the surface of choroid plexus epithelial cells and Met is additionally expressed at the brain endothelial cells of the blood-cerebrospinal fluid (CSF) and blood–brain barriers. Hence, the invasion of the CNS is facilitated by both InlA and InlB mechanisms [7].
Once internalized into the target cells in a primary vacuole, the next step in the infection cycle is the escape from the primary vacuole into the cell cytosol [79] (Figure 3). This vacuolar escape is mediated by the production of LLO [8,79]. This pore-forming cholesterol-dependent cytotoxin causes the rupture of the vacuole and release of the bacterial cells into the host cell cytosol [80]. In addition to LLO, L. monocytogenes also employs phospholipases, such as PI-PLC, that significantly enhance the lysis of the primary vacuole [52]. Following a period of intracellular replication inside infected cells, the production of ActA results in the formation of actin comet tails which facilitate bacterial motility inside the cells as well as the spread to uninfected cells through membrane protrusions [9]. The double membrane of the resulting secondary vacuole is degraded by LLO in collaboration with PC-PLC [9].

3.4. Clinical Outcomes of Invasive L. monocytogenes Infections

The clinical outcomes of listeriosis depend on the health status of the infected individual and are often correlated to underlying factors and comorbidities such as cancer, chronic renal, cardiovascular, and liver disease, multi-organ failure, and old age [81,82,83]. In neurolisterial infections, the most common symptoms include meningitis, meningoencephalitis, and rhombencephalitis [7]. For maternofetal listeriosis, the main clinical features include amniotic inflammation (amnionitis), preterm labor, stillbirths, and spontaneous abortions. In severe cases, widespread micro-abscesses and granulomatosis infantiseptica in newborns can occur [84]. Fever, diarrhea, influenza-like symptoms, multi-organ failure, and decompensated comorbidities are the most commonly reported clinical features associated with listerial septicemia [81]. In rare cases, infections can also affect a variety of organs and organ systems [85]. These infections normally involve the cardiovascular system (endocarditis) [86], respiratory tract infections (pleural infections and pneumonia) [87], biliary tract infections (cholecystitis, cholangitis, and biliary cyst infection) [88], and bone and joint infections, especially those involving orthopedic implant devices [89].

4. L. monocytogenes Stress Responses and Adaptation

Similar to all living organisms, the ability of L. monocytogenes to sense and respond to environmental changes is essential to its survival. Environmental conditions such as osmotic pressure shifts, temperature shifts, pH extremes, changing redox potential and fluctuating nutrient availability impose stress on microbial cells [10]. At their extremes, stress conditions can cause damage to the cellular structural components and disrupt the homeostatic balance inside microbial cells, resulting in cell death [11]. In many instances, microorganisms are exposed to mild stress levels that only reduce growth without causing loss of viability [90]. Due to the demand for minimally processed foods that preserve the natural freshness and nutritional quality, many foods are processed by the use of mild processing technologies that apply a combination of many sub-lethal stress treatments [91]. Despite the benefits of such approaches, exposure to sub-lethal stresses can induce the development of adaptive stress tolerance responses that enhance the survival of pathogens when exposed to subsequent lethal stress along the food value chain [15]. Many sub-lethal stress hurdles employed in food preservation have been proven to induce adaptive tolerance to lethal stress treatments in L. monocytogenes [92,93,94,95,96]. Exposure to sub-lethal acid at pH 5.0, sub-lethal heat at 46 °C, and sub-lethal H2O2 at 100 ppm H2O2 induces tolerance to lethal acid at pH 3.5; lethal heat at 63 °C and lethal H2O2 at 1000 ppm, respectively [95,97,98]. In addition to homologous adaptive responses, heterologous cross-adaptation between different stress factors also occurs [99]. For example, protection against lethal acid stress in L. monocytogenes can be induced by sub-lethal NaCl and heat stress exposures [96,97,98]. The development of adaptive responses has implications for pathogen survival in foods and, subsequently, in the GIT.

4.1. Adaptation to Stress in Foods and Food Processing Environments

The mechanisms responsible for the development of L. monocytogenes adaptive tolerance responses against the common environmental and food-related stresses (acid, osmotic, heat, cold, oxidative stress) have been elucidated [95,100,101,102,103,104]. Upon exposure to stress, L. monocytogenes modulates the transcription of stress response genes whose effect is to trigger cellular processes that allow the pathogen to survive and grow in the presence of stress [21]. The specific mechanisms of response to acid, osmotic, heat, cold, and oxidative stresses are briefly described in this section.

4.1.1. Osmotic Stress Adaptation

Osmotic stress results from changes in environmental osmolarity that disrupt the cellular osmotic balance [105]. Changes in environmental osmolarity can result from environmental salinity, desiccation and the use of hyperosmotic solutes in foods [106,107]. Extreme hyperosmotic conditions result in loss of cell turgor and cell death due to plasmolysis [105]. The ability of L. monocytogenes to withstand hyperosmotic conditions has been known for a long time [98,108]. In response to hyperosmotic conditions, the organism actively accumulates compatible solutes as a way of counterbalancing the negative effects of outward water movement. Compatible solutes are low-molecular-weight, highly soluble compounds that bear a neutral charge at physiological pH, whose accumulation inside the cells helps in restoring cell turgor, without affecting cytoplasmic function [109]. Although several compounds have been identified as potential osmoprotectants, glycine betaine (N,N,N-trimethylglycine) and carnitine (β-hydroxy-γ-N-trimethyl aminobutyrate) are the most potent at conferring osmoprotection on L. monocytogenes [110]. Notably, both compounds are not synthesized by L. monocytogenes but are fairly ubiquitous in foods of both plant and animal origin and, therefore, their intracellular accumulation is achieved by active transport from the environment [109,111].
The osmotic stress response is triggered by changes in osmotic pressure as the main signal [112]. However, the mechanism of signal sensing and transduction has only recently been elucidated [113]. The modulation of osmolyte transport and the expression of genes encoding osmolyte transporters is regulated Cyclic di-AMP (c-di-AMP) [105,113]. Two glycine betaine transporters (Gbu and BetL) and a single carnitine transporter OpuC have been known to respond to osmotic upshifts [109]. Gbu is an ATP-dependent transporter encoded by the gbu operon that mediates the uptake of glycine betaine in response to osmotic and cold stress [114]. BetL is a non-ATP-dependent secondary transporter encoded by betL, whose uptake of glycine betaine is coupled to Na+ symport [115]. Carnitine transport is mediated by the ATP-dependent transporter, OpuC, a product of the opuC operon that responds to both osmotic and cold stress [116].

4.1.2. Acid Stress Adaptation

Organic acids constitute one of the most frequently used preservatives in foods. Although there are several antimicrobial targets of acids [117,118,119], the primary antimicrobial effects result from the protonation of the cytoplasm and disruption of intracellular pH [120]. Two amino acid decarboxylation systems (the glutamate decarboxylase (GAD) and arginine deiminase (ADI)) have been known to protect L. monocytogenes against acid stress [102,104].
The GAD system depends on the enzyme glutamate decarboxylase, a product of the gadD operon which decarboxylates glutamate to produce γ-amino butyric acid (GABA) while consuming a proton and releasing a bicarbonate anion. The decarboxylation is coupled with an antiporter (GadT) that takes out the produced GABA while taking in glutamate [104]. L. monocytogenes produces three glutamate decarboxylase enzymes (GadD1, GadD2, and GadD3) and two antiporters (GadT1 and GadT2) that are encoded as pairs consisting of gadD1T1 and gadD2T2 operons in separate parts of the genome [104]. The genes have distinct functions in the acid stress response of L. monocytogenes. The expression of gadD1T1 is required for mild acid (pH 5.1) survival, while the gadD2T2 expression is needed for severe acid stress (pH 2.8), and therefore, is necessary for the adaptive acid tolerance response (ATR) [121].
The ADI system involves the conversion of arginine to ornithine accompanied by the production of ammonia and carbon dioxide [122]. As part of the system, an arginine-ornithine antiporter (protein ArcD encoded by arcD) facilitates the uptake of arginine in exchange for ornithine. Once inside the cell, the deimination of arginine by the enzyme arginine deiminase (encoded by the arcA) produces ammonia and citrulline. The latter is then converted to ornithine and carbamoyl phosphate through the enzyme ornithine carbamoyltransferase (encoded by arcB). Carbamoyl phosphate is subsequently converted to ammonia and carbon dioxide through the activity of carbamate kinase (encoded by arcC) [102]. This reaction reduces internal pH through the conversion of ammonia (NH3) to ammonium ions (NH4+) [123].

4.1.3. Heat Stress Adaptation

Thermal processing is an established method of food preservation, known for its lethality, especially at elevated temperatures. As a non-spore-former, L. monocytogenes is generally susceptible to heat stress, although it has been reported to exhibit thermotolerance upon exposure to heat shock at sublethal temperatures [124,125]. Moreover, heat resistance can be induced by exposure to acid, oxidative, alkali, and chlorine stresses [126,127]. The heat stress response is universal in all prokaryotes and is triggered by temperature up-shifts above the normal growth range. Its main effect is the protection of cellular proteins and enzymes against heat-induced denaturation that affects their physiological functions [101]. The heat shock response of L. monocytogenes involves the increased transcription of heat shock genes coding for three classes of heat shock proteins (HSPs) [128]. Of these three classes of HSPs, the expression of Class I and Class III proteins is a direct response to heat stress, while Class II proteins are general stress response proteins under the regulatory control of σB [101]. Class I HSPs are chaperones made up of the proteins, dnaK, dnaJ, groES, and groEL encoded in two operons (the dnaK and groEL-groES operons) [129,130]. Class III HSPs are ATP-dependent proteases (clpP, clpC, clpE, and clpB) involved in the proteolysis of misfolded proteins [13]. Under normal growth temperature, the expression of the Class I HSPs and Class III HSPs genes is prevented by HrcA and CtsR repression, respectively [101,131]. Under conditions of elevated temperatures, de-repression is achieved through the reduced DNA binding of repressors and improved binding of sigma factor A, leading to increased transcription [101].

4.1.4. Cold Stress Adaptation

Although L. monocytogenes is typically a mesophile, with an optimum growth temperature of 30–37 °C, the organism has a remarkable ability to multiply under low-temperature conditions [132]. While part of this psychrotrophic growth ability may be intrinsic, a significant part of it is induced by exposure to cold conditions [133]. At least three mechanisms are utilized by L. monocytogenes in response to cold stress-imposed challenges. These include the adjustment of the fatty acid composition of the cell membranes in order to maintain fluidity, the increased expression of cold shock proteins (CSP), and the accumulation of osmolytes and oligopeptides [103].
Upon exposure to low temperatures, the membrane of mesophilic bacteria changes from an elastic liquid crystalline state to a gel-phase state, resulting in the impairment of nutrient uptake [100]. The low-temperature growth propensity of L. monocytogenes is related to its ability to maintain membrane fluidity, which is necessary for nutrient transport [134]. The mechanism of cold stress adaptation involves the adjustment of membrane fluidity through the incorporation of unsaturated anteiso-branched-chain fatty acids (BCFA) [135]. Anteiso-BCFAs have a lower melting point than the analogous iso-BCFAs that account for >95% of the membrane fatty acid composition of L. monocytogenes cells growing at 37 °C [136]. A key determinant in the adjustment of membrane fluidity is the enzyme β-ketoacyl-acyl carrier protein synthase III (FabH) which catalyzes the initial condensation reaction between iso- and anteiso-branched α-keto acids and acetyl-coenzyme A [135,137].
CPSs belong to a family of small highly conserved and structurally related proteins that are widely distributed in the prokaryotic kingdom [100]. Within the genomes of L. monocytogenes, three families of CSP genes (CspA, CspB, and CspD coding for CpsA, CpsB and CpsD, respectively) have been found [138]. While these proteins are dispensable for growth at 37 °C, they are required for growth at 5–10 °C [139,140]. Using directed mutagenesis, Schmid et al. [139] observed that CspA is the main CSP required for low-temperature growth of L. monocytogenes. Although the exact functions of CSPs are still to be fully elucidated, the current postulation is that these proteins act as nucleic acid chaperones that bind RNA and DNA, thus, facilitating the control of processes such as replication, transcription, and translation within bacterial cells under cold stress [100]. This is presumably necessary to help the organisms overcome the challenges of DNA and RNA supercoiling, which is associated with low-temperature growth [100], coupled with the role of CSPs are RNA helicases, that bind to ribosomes and facilitate RNA maturation challenges at low temperatures [141]. Four DEAD-box RNA helicase genes have been found in the genome of L. monocytogenes [142]. Using knock-out mutants, the helicases were found to be necessary for L. monocytogenes cold growth [141,143].
L. monocytogenes cold stress adaptation also involves the accumulation of compatible solutes, glycine betaine, and carnitine, as well as oligopeptides as cryoprotectants [103]. The main osmolyte transporters Gbu, BetL and OpuC induced by osmotic stress are also induced by cold stress [144,145]. The accumulation of oligopeptides in L. monocytogenes is mediated by the oligopeptide permease transporter (OppA) encoded by the opp operon [146]. The exact roles of the accumulated osmolytes and oligopeptides in the cold stress response are unclear. Some posited roles include acting as cryoprotectants and stabilization of enzymes [103].

4.1.5. Oxidative Stress Adaptation

Oxidative stress results from the production and accumulation of reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, and singlet oxygen that cause damage to cellular molecules such as DNA, lipids, and proteins [147]. As a facultative anaerobe, L. monocytogenes is oxidative stress-tolerant. Catalase and superoxide dismutase encoded by the kat and sod genes, respectively, are the primary antioxidant enzymes produced by L. monocytogenes [148,149]. The two enzymes detoxify the superoxide anion and hydrogen peroxide generated by aerobic metabolism [150]. In addition to the detoxifying enzymes, L. monocytogenes possesses a metal-dependent peroxide sensor, PerR (peroxide repressor), that regulates the expression of peroxidase genes and genes for metal homeostasis [151]. The PerR regulon includes kat, fur (iron homeostasis regulator), hemA (haem biosynthesis), fri (iron-binding protein) and fvrA (iron efflux pump) [151,152].

4.2. Adaptation to Stress in the GIT

The successful colonization and subsequent GIT invasion by L. monocytogenes rely on the ability of the pathogen to overcome the harsh conditions associated with the innate defences of the GIT. The first physical stress encountered by L. monocytogenes in the GIT is the low pH of the stomach that the pathogen must deal with as it transits to the small intestines [153]. The critical role of acid stress adaptation in L. monocytogenes pathogenesis has been demonstrated through in vitro infection models of enterocyte-like cells and mice models [154,155]. The survival of stomach acidity is attributable to the expression of the GAD system [104]. The gadD2T2 operon, which is responsible for the ATR of L. monocytogenes induced by environmental acid stress exposure, is required for the survival in gastric fluid [104,121].
Once L. monocytogenes passes through the low pH of the stomach, it is faced with high osmotic stress and bile stress in the lumen of the small intestines [156]. The resistance to osmotic stress in the GIT has been attributed to the activation of the carnitine transporter opuC [116,140]. L. monocytogenes mutants with opuC gene deletions have been shown to exhibit limited pathogenicity in animal infection models, while the deletion of glycine betaine transporter genes gbu and betL do not seem to affect virulence [116,140]. The importance of carnitine as the preferred osmolyte in the GIT survival of L. monocytogenes is probably linked to its relative abundance in mammalian tissues [140]. Bile stress tolerance is a critical factor in L. monocytogenes GIT survival and colonization. The pathogen produces a bile salt hydrolase (BSH) enzyme (encoded by bsh) that catalyzes the hydrolysis of the amide bond between the bile acids (cholic acid and chenodeoxycholic acid) and the amino acid conjugates [157]. The enzymatic hydrolysis is complemented by an increased expression of the transporter protein BilE (a product of the bilE gene) which is responsible for bile exclusion [158].

5. Crosslink between Stress Responses and Virulence

5.1. Regulation of L. monocytogenes Stress Response

In L. monocytogenes, the general stress response alternative sigma factor B (SigB) modulates a reprogramming of gene expression that facilitates the survival and protection against harsh environmental conditions [12]. Since it was first described in L. monocytogenes three decades ago [159], several roles of SigB have been identified [160,161,162,163]. The identified regulon of this general stress response regulator encompasses more than 200 genes that are involved in environmental stress survival, metabolism, and virulence [20,164]. As a general stress response regulator, SigB mediates survival under a broad range of lethal stresses along the food value chain. Transcriptomic and mutagenesis experiments have shown that responses to the common environmental and food stress factors (acid, osmotic, heat, cold, oxidative stress and nutrient stress) are sigB-dependent [20,159,165,166,167]. Although SigB is the central transcriptional regulator of stress survival genes in L. monocytogenes, some alternative transcriptional regulators are also utilized in response to specific stress factors. For instance, the expression of Class I and Class III hsp genes relies on HrcA and CtsR proteins as negative regulators [101], while the peroxide repressor PerR regulates the expression of oxidative stress response genes [151].
In addition to regulating stress responses in the environment, SigB also modulates gene expression in response to stress conditions encountered along the oral infection route. sigB deletion mutants exhibit limited pathogenicity in orally infected model animals [168]. The SigB modulation of the gadD2T2 operon, opuC, bsh and bilE gene expression is critical to the survival of stomach acidity, intestinal osmotic and bile stresses, respectively, as a prerequisite for a successful intestinal invasion [116,121,157,158]. Besides its role in stress survival and adaptation, evidence shows that SigB also plays a critical role in the invasion of the intestinal barrier and initiation of infection [12,21]. Thus, the general stress response regulator facilitates a smooth transition from the environmental saprophytic life cycle to the pathogenic life cycle inside host cells.

Molecular Mechanisms of SigB-Dependent Regulation

The SigB protein is encoded by the sigB gene as part of an operon that includes seven other genes referred to as the regulation of sigma B (rsb) genes (rsbR, rsbS, rsbT, rsbU, rsbV, rsbW, and rsbX) coding for Rsb proteins [169]. The Rsb proteins are responsible for the detection of environmental stress signals and the regulatory cascade that controls the activity of SigB. The sensing and transduction of environmental signals is mediated by a 1.8 MDa supra-macromolecular stressosome consisting of a complex of RsbR-RsbS-RsbT proteins [12,170]. Although the exact mechanisms of stress sensing are not clearly understood, the current model is based on phosphorylation events by the sensor kinase RsbT and its subsequent release from the stressosome complex (Figure 4). RsbT subsequently activates RsbU, converting to an active phosphatase. Through its dephosphorylation activity, RsbU in turn activates RsbV [12,171]. In exponentially growing cells, the SigB protein exists as an inactive form bound to the anti-SigB protein, RsbW [169]. The activation of SigB is achieved by a partner-switching mechanism in which the release of RsbW is mediated by the binding of the dephosphorylated form of the anti-SigB protein, RsbV (Figure 4) [169].

5.2. Regulation of L. monocytogenes Virulence

The transition of L. monocytogenes from an environmental saprophyte to an intracellular pathogen is facilitated by changes in gene expression patterns from environmental survival-related genes to intracellular survival-related genes. Central to the transition is the role of the protein PrfA, encoded by the prfA gene [172]. PrfA is a 27 kDa member of the cyclic AMP receptor protein (Crp)/fumarate nitrate reductase regulator (Fnr) family of bacterial transcription factors [28,173]. The Crp/Fnr transcriptional activators are symmetrical homodimers consisting of an N-terminal cAMP binding domain and C-terminal DNA binding domain [28]. Its regulon includes a block of virulence genes (hly, actA, plcA, mpl, and plcB) encoded by the Listeria pathogenicity island 1 (LIPI-1) and the inlAB operon on a separate chromosomal locus [172,174,175]. Apart from the invasion proteins, inlA and inlB, the role of PrfA in L. monocytogenes pathogenesis is largely on the expression of virulence factors associated with the intracellular stage of the infection as well as the cell-to-cell spread [19,176]. Hence, the transcriptional regulator is activated once the pathogen is in the cytosol of host cells, switching the bacterial cells from the avirulent to the virulent state [176]. The signals and mechanisms that trigger prfA expression in the host cytosol have only become clearer in the last decade [177,178,179]. Branched chain amino acids (BCAA) and phosphorylated hexoses have been identified as the metabolic signals inside host cells [180,181]. An exception to the need for intracellular activation has been observed with L. monocytogenes mutants that constitutively express the prfA gene (prfA* mutants) [182,183]. Such prfA* mutants exhibit a high virulence in animal infection models. However, their environmental stress survival ability is poor [176]. PrfA activates transcription by binding to the PrfA box, a 14-bp A/T-rich palindromic nucleotide sequence located ~40 bp upstream of the transcriptional start sites of genes under its control [21].

5.3. Regulatory Intersection between Stress Response and Virulence

A plethora of evidence has shown that responses to stress in L. monocytogenes influence pathogenesis [150,154,184,185,186]. In most reports, the relationship between stress response and pathogenesis is attributed to adaptive tolerance responses that enable the pathogen to survive host innate defences in the GIT [15,16]. Along with the adaptive stress tolerance, the relationship can also be attributable to overlaps and direct interaction between the regulatory networks of stress and virulence [12,21]. Some of the currently understood mechanisms behind the interplay between the stress and virulence regulatory networks are described in this section. An illustration of the overlap and interactions between transcriptional regulators of stress and virulence is depicted in Figure 5.
Coregulation of the inlA/B operon, actA and bsh: The dispensability of SigB in the pathogenesis of L. monocytogenes is a fact that has been established for a long time [18,168]. The initial evidence for the role of SigB in L. monocytogenes pathogenesis was based on observations that sigB deletion mutants are avirulent on oral infection but are fully virulent when injected intravenously [168]. Subsequent elucidation of the role of SigB established that in addition to its stress regulon, this transcriptional regulator extends to the control of virulence genes inlA, inlB, and actA (Table 1) [58,187]. The overlapping regulatory controls of SigB and PrfA on the inlAB operon provide the connection between the stress response and virulence of the pathogen [156]. The biological significance of this coregulation of the inlAB operon has been explained in terms of the need to facilitate a transition from GIT survival to the invasion of the intestinal barrier, in which SigB is necessary for initiating infection in the intestinal phase before yielding the regulatory function to PrfA in the intracellular stages of infection [156]. Moreover, PrfA also extends its regulatory network to some stress response genes involved in the GIT survival phase (Table 1), such as the bsh gene [184,188]. Guariglia-Oropeza et al. [184] suggested a model where SigB-dependent gene expression plays a role in the survival of acid and osmotic stress exposures in the early stages of GIT infection before the subsequent induction of PrfA by the exposure to bile. This intestinal expression of PrfA regulon potentially primes L. monocytogenes for the subsequent intracellular stage of infection. While ActA is primarily a virulence factor necessary for the intracellular stage of L. monocytogenes infection, it is also produced in the extracellular environment, where it mediates aggregation and biofilm formation [26,58]. Within the intestinal lumen, actA expression is under the dual regulation of both SigB and PrfA and is necessary for GIT colonization [26,189].
SigB downregulation of prfA expression and maintenance of basal levels: A growing body of evidence indicates that the interactions between SigB and PrfA extend beyond the coregulation of the inlAB operon (Figure 5) [19,191]. Three transcriptional promoters (prfAP1, prfAP2 and prfAP3) are utilized in the control of prfA expression in L. monocytogenes. Of these, prfAP1 and prfAP2 are intragenic promoters located upstream of the prfA gene on the LPI-1 that are activated by the vegetative sigma factor A (for prfAP1) and both sigma factor A and SigB (for prfAP2) [192]. However, the biological significance of SigB regulation of prfA expression has not been easy to establish [19]. The current hypothesis is that SigB regulation through the prfAP2 promoter may facilitate the downregulation of prfA transcription [19,28]. The repression is postulated to keep a basal level of PrfA that allows for a sensitive and rapid shift from the avirulent state to a virulent state once inside host cells [28]. Thus far, the main mechanism for the upregulation of prfA transcription inside host cells appears to be the positive autoregulatory feedback loop through the prfAP3 promoter [19]. The signal that triggers the upregulation of prfA transcription inside host cells remains unclear. One established observation is the role of temperature in the prfA expression [193,194]. In L. monocytogenes, a thermosensor located in the 5’-untranslated region (5′-UTR) of the prfA mRNA transcript allows for the translation of transcript at 37 °C, while preventing translation at temperatures <30 °C [195].
The metabolic regulator CodY as a link between SigB and PrfA networks: CodY is a Gram-positive bacterial metabolic regulator that responds to intracellular Guanosine-5’-triphosphate (GTP) concentration as an indicator of nutrient stress [196]. Under conditions of nutrient availability, CodY represses sigB expression, while activating the stress response regulator under conditions of nutrient stress [179]. Apart from GTP as the nutrient stress signal, CodY also responds to the cellular concentrations of branched chain amino acids (BCAA) [180]. Due to the low BCAA concentrations in host cells during infection, CodY plays a critical role in the biosynthesis of BCAAs through the upregulation of the ilv (isoleucine, leucine and valine (ILV)) operon [180]. Simultaneously, CodY results in an increased expression of virulence gene expression through a direct upregulation of prfA, while also causing an increased sigB expression [179]. Thus, the metabolic regulator acts as a link between L. monocytogenes metabolism, stress response, and pathogenesis (Figure 5) [178,197].
Glutathione allosteric activation of PrfA as an indirect link between SigB and PrfA networks: Similar to other Crp/Fnr family proteins, PrfA requires a co-factor to improve its DNA binding at promoter sequences [178]. In recent years, the tripeptide glutathione (GSH) has been identified as a post-translational activator of PrfA through allosteric mechanisms [198,199]. In addition to the direct role of SigB in the transcription of prfA, the stress response regulator also plays some indirect roles in stimulating prfA expression. Through the activity of the enzyme glutathione synthase (encoded by the gshF gene), L. monocytogenes can endogenously synthesize glutathione [200]. However, due to its antioxidant action, GSH is oxidized to GSSG. To maintain a healthy oxidative state, L. monocytogenes produces the SigB-regulated glutathione reductase (encoded by lmo1433) to modulate the GSH/GSSG ratio [17]. Thus, SigB contributes indirectly to PrfA activity by maintaining high levels of GSH reductase [12].
Along with the activation of prfA, there is also evidence to suggest that some stress response proteins of L. monocytogenes are involved in the post-transcriptional modification of some virulence factors [185,201]. For instance, Eshwar et al. [185] showed that cspABD deletion mutants could not produce the actin polymerization protein ActA, while Schärer et al. [201] made a similar observation with LLO production. Based on their observation, Eshwar et al. [185] hypothesized that the Csp proteins could be linked to the regulation of virulence gene expression at both transcriptional and post-transcriptional levels in L. monocytogenes.

6. Strain and Lineage Variability in Stress Response and Virulence

L. monocytogenes exhibits great heterogeneity within the species. The species is divided into four evolutionary lineages (designated lineages I, II, III, and IV), and 13 serotypes [202,203]. Additionally, using multilocus sequence typing (MLST) and whole-genome sequencing analysis, the species is divided into >100 clonal complexes (CCs) and sub-lineages (SLs) [204,205,206]. Among the lineages and serotypes, heterogeneity also exists with respect to virulence and ecological niche preferences [27,207]. Three serotypes belonging to lineage I (4b and 1/2b) and lineage II (1/2a) account for >95% of human listeriosis cases [208,209]. Furthermore, among the serotypes associated with human disease, serotype 4b strains are the most frequently implicated in severe clinical outcomes such as brain and placental infections [209,210]. On the other hand, lineage II strains are predominant in foods [209,211].
The molecular basis of L. monocytogenes strain and lineage virulence heterogeneity has been deciphered from the genetic differences between the so-called hypervirulent (serotype 4b, lineage I) and the hypovirulent (lineage II) strains [27,208]. Based on single nucleotide polymorphisms (SNPs) and multilocus genotyping (MLGT) using virulence (such as inlA, inlB; hly, plcC; actA) and sigB as well as whole-genome sequencing, several studies have shown that lineage II strains carry numerous mutations in their inlA genes that lead to premature stop codons and the production of truncated forms of inlA [212,213,214]. Consequently, despite their frequent occurrence in foods, lineage II strains are hypovirulent due to their inability to express a functional InlA protein needed for a successful systemic infection [27]. Apart from the core virulence genes encoded on LIPI-1 and the inlAB islet universally present in all L. monocytogenes strains, some lineage I strains harbor an extra set of virulence genes (the Listeria Pathogenicity Island 3 (LIPI-3)) [215,216]. LIPI-3 carries a gene cluster that includes the llsA gene conceding for the synthesis of Listeriolysin S (LLS), a bacteriocin whose function is to inhibit host microbiota during infection [216]. The absence of the LIPI-3 in the genomes of lineage II strains and its presence in the sub-lineages of lineage I (4b serotype) strains suggests that it is the main factor behind the hypervirulence of serotype 4b strains [27,204].
With respect to lineage II strains, their overrepresentation in the food environment is presumed to be a function of their ability to withstand environmental stress [203]. Available evidence shows that stress resistance phenotypes in L. monocytogenes are linked to genetic lineages, with lineage II strains particularly showing a better adaptation to environmental stresses such as salt, acid, and heat [217,218]. Using comparative genomics, of 174 clinical and food isolates, Pirone-Davies et al. [219] identified eight plasmid-borne genes uniquely associated with lineage II strains from food. These genes included cadmium resistance genes cadA and cadC, a multi-drug resistance gene ebrB, and a quaternary ammonium compound resistance gene qac [219]. Plasmid-harboring L. monocytogenes strains were found to be persistent in food processing environments and tolerant to benzalkonium chloride, elevated temperature, salinity, and acidic environments [220,221,222].
The near-total lack of association of lineage III strains with either foods or human infections is a subject that is still to be fully elucidated. A pan-genome analysis of 26 strains representing lineages I, II, and III, identified 86 disparately distributed genes highly conserved in lineages I and II genomes but highly divergent or absent in lineage III genomes [208]. Among the disparately distributed genes were genes involved in carbohydrate metabolism (phosphotransferase system (PTS)) and transcription factors [208]. Cerutti et al. [223] also identified genes for small regulatory RNAs that co-evolved with genes for pathogenicity and host interaction present in the genomes of lineage I and II strains but missing in the genomes of lineage III strains. Thus, reinforcing the hypothesis that lineage III strains evolved by loss of virulence and metabolic functions [208,223].

7. Conclusions and Future Perspectives

Adaptive stress tolerance responses play a critical role in the pathogenicity of L. monocytogenes. While stress adaptation is primarily a mechanism of environmental survival, the processes play a role in protecting the organism against the innate defence systems of the GIT. Furthermore, the transcriptional regulator of environmental stress adaptation, SigB, also has some concurrent effects on the expression of virulence factors that are also under the virulence regulator, PrfA. In parallel with the SigB regulatory effect on virulence genes, PrfA also exerts a synchronic effect on stress response genes for survival in the GIT. The regulatory overlap between the stress response and virulence serves as a point of coordination that facilitates a smooth transition from the avirulent saprophytic survival state to a virulent pathogenic state once inside the host.
Apart from the overlapping functions, direct and indirect interactions between the two transcriptional regulators account for the intricate link between the regulatory networks for stress response and virulence. While a significant amount of information is now available on the expressional crosstalk between SigB and PrfA as the respective central regulators of stress response and virulence, the full understanding of these molecular interactions is still elusive. As a prominent foodborne pathogen, an understanding of the molecular basis of L. monocytogenes stress survival and its influence on pathogenesis is critical to the identification of potential targets for the control of the pathogen through the interruption of its transmission and infection cycle.

Author Contributions

Conceptualization, T.S. and E.M.B.; writing—original draft preparation, T.S.; writing—review and editing, T.S. and E.M.B.; supervision, E.M.B. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Linke, K.; Rückerl, I.; Brugger, K.; Karpiskova, R.; Walland, J.; Muri-Klinger, S.; Tichy, A.; Wagner, M.; Stessl, B. Reservoirs of Listeria species in three environmental ecosystems. Appl. Environ. Microbiol. 2014, 80, 5583–5592. [Google Scholar] [CrossRef] [Green Version]
  2. Halbedel, S.; Wilking, H.; Holzer, A.; Kleta, S.; Fischer, M.A.; Lüth, S.; Pietzka, A.; Huhulescu, S.; Lachmann, R.; Krings, A.; et al. Large nationawide outbreak of invasive listeriosis associated with blood sausage, Germany, 2018–2019. Emerg. Infect. Dis. 2020, 26, 1456–1464. [Google Scholar] [CrossRef]
  3. Thomas, J.; Govender, N.; McCarthy, K.M.; Erasmus, L.K.; Doyle, T.J.; Allam, M.; Ismail, A.; Ramalwa, N.; Sekwadi, P.; Ntshoe, G.; et al. Outbreak of listeriosis in South Africa associated with processed meat. N. Engl. J. Med. 2020, 382, 632–643. [Google Scholar] [CrossRef]
  4. Self, J.L.; Conrad, A.; Stroika, S.; Jackson, A.; Whitlock, L.; Jackson, K.A.; Al, J.L.S.E.; Wellman, A.; Fatica, M.K.; Bidol, S.; et al. Multistate outbreak of listeriosis associated with packaged leafy green salads, United States and Canada, 2015–2016. Emerg. Infect. Dis. 2019, 25, 1461–1468. [Google Scholar] [CrossRef] [PubMed]
  5. Warriner, K.; Namvar, A. What is the hysteria with Listeria? Trends Food Sci. Technol. 2009, 20, 245–254. [Google Scholar] [CrossRef]
  6. Quereda, J.J.; Morón-García, A.; Palacios-Gorba, C.; Dessaux, C.; Portillo, F.G.-D.; Pucciarelli, M.G.; Ortega, A.D. Pathogenicity and virulence of Listeria monocytogenes: A trip from environmental to medical microbiology. Virulence 2021, 12, 2509–2545. [Google Scholar] [CrossRef] [PubMed]
  7. Disson, O.; Lecuit, M. Targeting of the central nervous system by Listeria monocytogenes. Virulence 2012, 3, 213–221. [Google Scholar] [CrossRef] [Green Version]
  8. Pizarro-Cerdá, J.; Cossart, P. Invasion of host cells by Listeria monocytogenes. In Listeria monocytogenes: Pathogenesis and Host Response; Goldfine, H., Shen, H., Eds.; Springer Science Business Media, LLC: Berlin, Germany, 2007; pp. 159–176. [Google Scholar]
  9. Cossart, P.; Lebreton, A. A trip in the “new Microbiology” with the bacterial pathogen Listeria monocytogenes. FEBS Lett. 2014, 588, 2437–2445. [Google Scholar] [CrossRef] [Green Version]
  10. Wiktorczyk-Kapischke, N.; Skowron, K.; Grudlewska-Buda, K.; Wałecka-Zacharska, E.; Korkus, J.; Gospodarek-Komkowska, E. Adaptive response of Listeria monocytogenes to the stress factors in the food processing environment. Front. Microbiol. 2021, 12, 710085. [Google Scholar] [CrossRef] [PubMed]
  11. Vorob’eva, L.I. Stressors, stress reactions, and survival of bacteria: A review. Appl. Biochem. Microbiol. 2004, 40, 217–224. [Google Scholar] [CrossRef]
  12. Guerreiro, D.N.; Arcari, T.; O’Byrne, C.P. The σB-mediated general stress response of Listeria monocytogenes: Life and death decision making in a pathogen. Front. Microbiol. 2020, 11, 1505. [Google Scholar] [CrossRef]
  13. Bucur, F.I.; Grigore-Gurgu, L.; Crauwels, P.; Riedel, C.U.; Nicolau, A.I. Resistance of Listeria monocytogenes to stress conditions encountered in food and food processing environments. Front. Microbiol. 2018, 9, 2700. [Google Scholar] [CrossRef] [Green Version]
  14. Fang, F.C.; Frawley, E.R.; Tapscott, T.; Vázquez-Torres, A. Bacterial stress responses during host infection. Cell Host Microbe. 2016, 20, 133–143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Begley, M.; Hill, C. Stress adaptation in foodborne pathogens. Annu. Rev. Food Sci. Technol. 2015, 6, 191–210. [Google Scholar] [CrossRef]
  16. Gahan, C.G.M.; Hill, C. Listeria monocytogenes: Survival and adaptation in the gastrointestinal tract. Front. Cell Infect. Microbiol. 2014, 4, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Kazmierczak, M.J.; Mithoe, S.C.; Boor, K.J.; Wiedmann, M. Listeria monocytogenes σB regulates stress response and virulence functions. J. Bacteriol. 2003, 185, 5722–5734. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Kazmierczak, M.J.; Wiedmann, M.; Boor, K.J. Contributions of Listeria monocytogenes σB and PrfA to expression of virulence and stress reponse genes during extra- and intracellular growth. Microbiology 2006, 152, 1827–1838. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Gaballa, A.; Guariglia-Oropeza, V.; Wiedmann, M.; Boor, K.J. Cross talk between SigB and PrfA in Listeria monocytogenes facilitates transitions between extra- and intracellular environments. Microbiol. Mol. Biol. Rev. 2019, 83, e00034-19. [Google Scholar] [CrossRef] [PubMed]
  20. Liu, Y.; Orsi, R.H.; Gaballa, A.; Wiedmann, M.; Boor, K.J.; Guariglia-Oropeza, V. Systematic review of the Listeria monocytogenes σB regulon supports a role in stress response, virulence and metabolism. Future Microbiol. 2019, 14, 801–828. [Google Scholar] [CrossRef] [Green Version]
  21. Tiensuu, T.; Guerreiro, D.N.; Oliveira, A.H.; O’Byrne, C.; Johansson, J. Flick of a switch: Regulatory mechanisms allowing Listeria monocytogenes to transition from a saprophyte to a killer. Microbiology 2019, 165, 819–833. [Google Scholar] [CrossRef] [PubMed]
  22. Drolia, R.; Bhunia, A.K. Crossing the intestinal barrier via Listeria adhesion protein and Internalin A. Trends Microbiol. 2019, 27, 408–425. [Google Scholar] [CrossRef]
  23. McMullen, P.D.; Freitag, N.E. Listeria monocytogenes. In Molecular Medical Microbiology, 2nd ed.; Tang, Y.-W., Sussman, M., Liu, D., Poxton, I., Schwartzman, J., Eds.; Academic Press, Elsevier Ltd.: New York, NY, USA, 2014; pp. 1345–1361. [Google Scholar]
  24. Lecuit, M. Listeria monocytogenes, a model in infection biology. Cell. Microbiol. 2020, 22, e13186. [Google Scholar] [CrossRef] [Green Version]
  25. Liu, D.; Yin, X.; Olyha, S.J.; Nascimento, M.S.L.; Chen, P.; White, T.; Gowthaman, U.; Zhang, T.; Gertie, J.A.; Zhang, B.; et al. IL-10-dependent crosstalk between murine marginal zone B cells, macrophages, and CD8α+ dendritic cells promotes Listeria monocytogenes infection. Immunity 2019, 51, 64–76. [Google Scholar] [CrossRef]
  26. Travier, L.; Guadagnini, S.; Gouin, E.; Dufour, A.; Chenal-Francisque, V.; Cossart, P.; Olivo-Marin, J.C.; Ghigo, J.M.; Disson, O.; Lecuit, M. ActA promotes Listeria monocytogenes aggregation, intestinal colonization and carriage. PLoS Pathog. 2013, 9, e1003131. [Google Scholar] [CrossRef] [Green Version]
  27. Disson, O.; Moura, A.; Lecuit, M. Making sense of the biodiversity and virulence of Listeria monocytogenes. Trends Microbiol. 2021, 29, 811–822. [Google Scholar] [CrossRef] [PubMed]
  28. de las Heras, A.; Cain, R.J.; Bielecka, M.K.; Vázquez-Boland, J.A. Regulation of Listeria virulence: PrfA master and commander. Curr. Opin. Microbiol. 2011, 14, 118–127. [Google Scholar] [CrossRef] [PubMed]
  29. Jagadeesan, B.; Littlejohn, A.E.F.; Amalaradjou, M.A.R.; Singh, A.K.; Mishra, K.K.; La, D.; Kihara, D.; Bhunia, A.K. N-Terminal Gly224-Gly411 domain in Listeria adhesion protein interacts with host receptor HsP60. PLoS ONE 2011, 6, e20694. [Google Scholar] [CrossRef]
  30. Pandiripally, V.K.; Westbrook, D.G.; Sunki, G.R.; Bhunia, A.K. Surface protein p104 is involved in adhesion of Listeria monocytogenes to human intestinal cell line, Caco-2. J. Med. Microbiol. 1999, 48, 117–124. [Google Scholar] [CrossRef] [Green Version]
  31. Burkholder, K.M.; Bhunia, A.K. Listeria monocytogenes uses Listeria adhesion protein (LAP) to promote bacterial transepithelial translocation and induces expression of LAP receptor Hsp60. Infect. Immun. 2010, 78, 5062–5073. [Google Scholar] [CrossRef] [Green Version]
  32. Jagadeesan, B.; Koo, O.K.; Kim, K.P.; Burkholder, K.M.; Mishra, K.K.; Aroonnual, A.; Bhunia, A.K. LAP, an alcohol acetaldehyde dehydrogenase enzyme in Listeria, promotes bacterial adhesion to enterocyte-like Caco-2 cells only in pathogenic species. Microbiology 2010, 156, 2782–2795. [Google Scholar] [CrossRef] [PubMed]
  33. Burkholder, K.M.; Kim, K.-P.; Mishra, K.K.; Medina, S.; Hahm, B.-K.; Kim, H.; Bhunia, A.K. Expression of LAP, a SecA2-dependent secretory protein, is induced under anaerobic environment. Microbes Infect. 2009, 11, 859–867. [Google Scholar] [CrossRef]
  34. Drolia, R.; Tenguria, S.; Durkes, A.C.; Turner, J.R.; Bhunia, A.K. Listeria adhesion protein induces intestinal epithelial barrier dysfunction for bacterial translocation. Cell Host Microbe 2018, 23, 470–484.e7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Hymes, J.P.; Klaenhammer, T.R. Stuck in the middle: Fibronectin-binding proteins in Gram-positive bacteria. Front. Microbiol. 2016, 7, 1504. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Henderson, B.; Nair, S.; Pallas, J.; Williams, M.A. Fibronectin: A multidomain host adhesin targeted by bacterial fibronectin-binding proteins. FEMS Microbiol. Rev. 2011, 35, 147–200. [Google Scholar] [CrossRef] [Green Version]
  37. Dramsi, S.; Bourdichon, F.; Cabanes, D.; Lecuit, M.; Fsihi, H.; Cossart, P. FbpA, a novel multifunctional Listeria monocytogenes virulence factor. Mol. Microbiol. 2004, 53, 639–649. [Google Scholar] [CrossRef]
  38. Gaillard, J.-L.; Berche, P.; Frehel, C.; Gouln, E.; Cossart, P. Entry of L. monocytogenes into cells is mediated by internalin, a repeat protein reminiscent of surface antigens from Gram-positive cocci. Cell 1991, 65, 1127–1141. [Google Scholar] [CrossRef]
  39. Ireton, K.; Mortuza, R.; Gyanwali, G.C.; Gianfelice, A.; Hussain, M. Role of internalin proteins in the pathogenesis of Listeria monocytogenes. Mol. Microbiol. 2021, 116, 1407–1419. [Google Scholar] [CrossRef]
  40. Schubert, W.-D.; Urbanke, C.; Ziehm, T.; Beier, V.; Machner, M.P.; Domann, E.; Wehland, J.; Chakraborty, T.; Heinz, D.W. Structure of internalin, a major invasion protein of Listeria monocytogenes, in complex with its human receptor E-cadherin. Cell 2002, 111, 825–836. [Google Scholar] [CrossRef] [Green Version]
  41. Dellafiora, L.; Filipello, V.; Dall’Asta, C.; Finazzi, G.; Galaverna, G.; Losio, M.N. A structural study on the Listeria monocytogenes internalin A—Human E-cadherin interaction: A molecular tool to investigate the effects of missense mutations. Toxins 2020, 12, 60. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Braun, L.; Dramsi, S.; Dehoux, P.; Bierne, H.; Lindahl, G.; Cossart, P. InIB: An invasion protein of Listeria monocytogenes with a novel type of surface association. Mol. Microbiol. 1997, 25, 285–294. [Google Scholar] [CrossRef] [PubMed]
  43. Bierne, H.; Sabet, C.; Personnic, N.; Cossart, P. Internalins: A complex family of leucine-rich repeat-containing proteins in Listeria monocytogenes. Microbes Infect. 2007, 9, 1156–1166. [Google Scholar] [CrossRef] [PubMed]
  44. Pizarro-Cerdá, J.; Kühbacher, A.; Cossart, P. Entry of Listeria monocytogenes in mammalian epithelial cells: An updated view. Cold Spring Harb. Perspect. Med. 2012, 2, a010009. [Google Scholar] [CrossRef]
  45. Milohanic, E.; Glaser, P.; Coppée, J.-Y.; Frangeul, L.; Vega, Y.; Vázquez-Boland, J.A.; Kunst, F.; Cossart, P.; Buchrieser, C. Transcriptome analysis of Listeria monocytogenes identifies three groups of genes differently regulated by PrfA. Mol. Microbiol. 2003, 47, 1613–1625. [Google Scholar] [CrossRef] [Green Version]
  46. Hamon, M.; Ribet, D.; Stavru, F.; Cossart, P. Listeriolysin O: The Swiss army knife of Listeria. Trends Microbiol. 2012, 20, 360–368. [Google Scholar] [CrossRef]
  47. Hof, H. Virulence of different strains of Listeria monocytogenes serovar 1/2a. Med. Microbiol. Immunol. 1984, 173, 207–218. [Google Scholar] [CrossRef]
  48. Geoffroy, C.; Gaillard, J.-L.; Alouf, J.E.; Berche, P. Purification, characterization, and toxicity of thesulfhydry-activated hemolysin Listerion O from Listeria monocytogenes. Infect. Immun. 1987, 55, 1641–1646. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Kuhn, M.; Kathariou, S.; Goebel, W. Hemolysin supports survival but not entry of the intracellular bacterium Listeria monocytogenes. Infect. Immun. 1988, 56, 79–82. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Phelps, C.C.; Vadia, S.; Arnett, E.; Tan, Y.; Zhang, X.; Pathak-Sharma, S.; Gavrilin, M.A.; Seveau, S. Relative roles of Listeriolysin O, InlA, and InlB in Listeria monocytogenes uptake by host cells. Infect. Immun. 2018, 86, e00555-18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Camilli, A.; Goldfine, H.; Portnoy, D.A. Listeria monocytogenes mutants lacking phosphatidylinositol-specific phospholipase C are avirulent. J. Exp. Med. 1991, 173, 751–754. [Google Scholar] [CrossRef] [Green Version]
  52. Smith, G.A.; Marquis, H.; Jones, S.; Johnston, N.C.; Portnoy, D.A.; Goldfine, H. The two distinct phospholipases C of Listeria monocytogenes have overlapping roles in escape from a vacuole and cell-to-cell spread. Infect. Immun. 1995, 63, 4231–4237. [Google Scholar] [CrossRef] [Green Version]
  53. Poussin, M.A.; Goldfine, H. Involvement of Listeria monocytogenes phosphatidylinositol-specific phospholipase C and host protein kinase C in permeabilization of the macrophage phagosome. Infect. Immun. 2005, 73, 4410–4413. [Google Scholar] [CrossRef] [Green Version]
  54. Gründling, A.; Gonzalez, M.D.; Higgins, D.E. Requirement of the Listeria monocytogenes broad-Range phospholipase PC-PLC during infection of human epithelial cells. J. Bacteriol. 2003, 185, 6295–6307. [Google Scholar]
  55. Coffey, A.; Burg, B.V.D.; Veltman, R.; Abee, T. Characteristics of the biologically active 35-kDa metalloprotease virulence factor from Listeria monocytogenes. J. Appl. Microbiol. 2000, 88, 132–141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Suárez, M.; González-Zorn, B.; Vega, Y.; Chico-Calero, I.; Vázquez-Boland, J.A. A role for ActA in epithelial cell invasion by Listeria monocytogenes. Cell. Microbiol. 2001, 3, 853–864. [Google Scholar] [CrossRef] [PubMed]
  57. Kocks, C.; Hellio, R.; Gounon, P.; Ohayon, H.; Cossart, P. Polarized distribution of Listeria monocytogenes surface protein ActA at the site of directional actin assembly. J. Cell Sci. 1993, 105, 699–710. [Google Scholar] [CrossRef] [PubMed]
  58. Travier, L.; Lecuit, M. Listeria monocytogenes ActA: A new function for a “classic” virulence factor. Curr. Opin. Microbiol. 2014, 17, 53–60. [Google Scholar] [CrossRef] [PubMed]
  59. Skoble, J.; Auerbuch, V.; Goley, E.D.; Welch, M.D.; Portnoy, D.A. Pivotal role of VASP in Arp2/3 complex-mediated actin nucleation, actin branch-formation, and Listeria monocytogenes motility. J. Cell Biol. 2001, 155, 89–100. [Google Scholar] [CrossRef] [PubMed]
  60. Kühn, S.; Enninga, J. The actin comet guides the way: How Listeria actin subversion has impacted cell biology, infection biology and structural biology. Cell. Microbiol. 2020, 22, e13190. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  61. Maurella, C.; Gallina, S.; Ru, G.; Adriano, D.; Bellio, A.; Bianchi, D.M.; Chiavacci, L.; Crescio, M.I.; Croce, M.; D'Errico, V.; et al. Outbreak of febrile gastroenteritis caused by Listeria monocytogenes 1/2a in sliced cold beef ham, Italy, May 2016. Eurosurveillance 2018, 23, 17–00155. [Google Scholar] [CrossRef]
  62. Ooi, S.T.; Lorber, B. Gastroenteritis due to Listeria monocytogenes. Clin. Infect. Dis. 2005, 40, 1327–1332. [Google Scholar] [CrossRef] [PubMed]
  63. Jacks, A.; Pihlajasaari, A.; Vahe, M.; Myntti, A.; Kaukoranta, S.-S.; Elomaa, N.; Salmenlinna, S.; Rantala, L.; Lahti, K.; Huusko, S.; et al. Outbreak of hospital-acquired gastroenteritis and invasive infection caused by Listeria monocytogenes, Finland, 2012. Epidemiol. Infect. 2016, 144, 2732–2742. [Google Scholar] [CrossRef] [Green Version]
  64. Sim, J.; Hood, D.; Finnie, L.; Wilson, M.; Graham, C.; Brett, M.; Hudson, J. Series of incidents of Listeria monocytogenes non-invasive febrile gastroenteritis involving ready-to-eat meats. Lett. Appl. Microbiol. 2002, 35, 409–413. [Google Scholar] [CrossRef]
  65. Halbedel, S.; Prager, R.; Banerji, S.; Kleta, S.; Trost, E.; Nishanth, G.; Alles, G.; Hölzel, C.; Schlesiger, F.; Pietzka, A.; et al. A Listeria monocytogenes ST2 clone lacking chitinase ChiB from an outbreak of non-invasive gastroenteritis. Emerg. Microbes Infect. 2019, 8, 17–28. [Google Scholar] [CrossRef] [Green Version]
  66. Radoshevich, L.; Cossart, P. Listeria monocytogenes: Towards a complete picture of its physiology and pathogenesis. Nat. Rev. Microbiol. 2018, 16, 32–46. [Google Scholar] [CrossRef]
  67. Nikitas, G.; Deschamps, C.; Disson, O.; Niault, T.; Cossart, P.; Lecuit, M. Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin. J. Exp. Med. 2011, 208, 2263–2277. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Pentecost, M.; Otto, G.; Theriot, J.; Amieva, M.R. Listeria monocytogenes invades the epithelial junctions at sites of cell extrusion. PLoS Pathog. 2006, 2, 0029–0040. [Google Scholar] [CrossRef] [Green Version]
  69. Bonazzi, M.; Lecuit, M.; Cossart, P. Listeria monocytogenes internalin and E-cadherin: From structure to pathogenesis. Cell. Microbiol. 2009, 11, 693–702. [Google Scholar] [CrossRef] [PubMed]
  70. Saila, S.; Gyanwali, G.C.; Hussain, M.; Gianfelice, A.; Ireton, K. The host GTPase Arf1 and its effectors AP1 and PICK1 stimulate actin polymerization and exocytosis to promote entry of Listeria monocytogenes. Infect. Immun. 2020, 88, e00578-19. [Google Scholar] [CrossRef] [PubMed]
  71. Holch, A.; Ingmer, H.; Licht, T.R.; Gram, L. Listeria monocytogenes strains encoding premature stop codons in inlA invade mice and guinea pig fetuses in orally dosed dams. J. Med. Microbiol. 2013, 62, 1799–1806. [Google Scholar] [CrossRef]
  72. Gelbíčová, T.; Koláčková, I.; Pantůček, R.; Karpíšková, R. A novel mutation leading to a premature stop codon in inlA of Listeria monocytogenes isolated from neonatal listeriosis. New Microbiol. 2015, 38, 293–296. [Google Scholar]
  73. Hase, K.; Kawano, K.; Nochi, T.; Pontes, G.S.; Fukuda, S.; Ebisawa, M.; Kadokura, K.; Tobe, T.; Fujimura, Y.; Kawano, S.; et al. Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response. Nature 2009, 462, 226–230. [Google Scholar] [CrossRef] [PubMed]
  74. Rey, C.; Chang, Y.-Y.; Latour-Lambert, P.; Varet, H.; Proux, C.; Legendre, R.; Coppée, J.-Y.; Enninga, J. Transcytosis subversion by M cell-to-enterocyte spread promotes Shigella flexneri and Listeria monocytogenes intracellular bacterial dissemination. PLoS Pathog. 2020, 16, e1008446. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Marco, A.J.; Altimira, J.; Prats, N.; López, S.; Dominguez, L.; Domingo, M.; Briones, V. Penetration of Listeria monocytogenes in mice infected by the oral route. Microb. Pathog. 1997, 23, 255–263. [Google Scholar] [CrossRef] [PubMed]
  76. Corr, S.; Hill, C.; Gahan, C.G. An in vitro cell-culture model demonstrates internalin- and hemolysin-independent translocation of Listeria monocytogenes across M cells. Microb. Pathog. 2006, 41, 241–250. [Google Scholar] [CrossRef] [PubMed]
  77. Charlier, C.; Disson, O.; Lecuit, M. Maternal-neonatal listeriosis. Virulence 2020, 11, 391–397. [Google Scholar] [CrossRef]
  78. Disson, O.; Grayo, S.; Huillet, E.; Nikitas, G.; Langa-Vives, F.; Dussurget, O.; Ragon, M.; Le Monnier, A.; Babinet, C.; Cossart, P.; et al. Conjugated action of two species-specific invasion proteins for fetoplacental listeriosis. Nat. Lett. 2008, 455, 1114–1118. [Google Scholar] [CrossRef] [PubMed]
  79. Kortebi, M.; Milohanic, E.; Mitchell, G.; Péchoux, C.; Prevost, M.-C.; Cossart, P.; Bierne, H. Listeria monocytogenes switches from dissemination to persistence by adopting a vacuolar lifestyle in epithelial cells. PLoS Pathog. 2017, 13, e1006734. [Google Scholar] [CrossRef] [PubMed]
  80. Schnupf, P.; Portnoy, D.A. Listeriolysin O: A phagosome-specific lysin. Microbes Infect. 2007, 9, 1176–1187. [Google Scholar] [CrossRef] [PubMed]
  81. Charlier, C.; Perrodeau, É.; Leclercq, A.; Cazenave, B.; Pilmis, B.; Henry, B.; Lopes, A.; Maury, M.M.; Moura, A.; Goffinet, F.; et al. Clinical features and prognostic factors of listeriosis: The MONALISA national prospective cohort study. Lancet Infect. Dis. 2017, 17, 510–519. [Google Scholar] [CrossRef]
  82. de Noordhout, C.M.; Devleesschauwer, B.; Angulo, F.J.; Verbeke, G.; Haagsma, J.; Kirk, M.; Havelaar, A.; Speybroeck, N. The global burden of listeriosis: A systematic review and meta-analysis. Lancet Infect. Dis. 2014, 14, 1073–1082. [Google Scholar] [CrossRef] [Green Version]
  83. Scobie, A.; Kanagarajah, S.; Harris, R.J.; Byrne, L.; Amar, C.; Grant, K.; Godbole, G. Mortality risk factors for listeriosis—A 10 year review of non-pregnancy associated cases in England 2006–2015. J. Infect. 2019, 78, 208–214. [Google Scholar] [CrossRef] [PubMed]
  84. Wadhwa Desai, R.; Smith, M.A. Pregnancy-related listeriosis. Birth Defects Res. 2017, 109, 324–335. [Google Scholar] [CrossRef] [Green Version]
  85. Lepe, J.A. Current aspects of listeriosis. Med. Clínica 2020, 154, 453–458. [Google Scholar] [CrossRef] [PubMed]
  86. Shoai-Tehrani, M.; Pilmis, B.; Maury, M.M.; Robineau, O.; Disson, O.; Jouvion, G.; Coulpier, G.; Thouvenot, P.; Bracq-Dieye, H.; Valès, G.; et al. Listeria monocytogenes-associated endovascular infections: A study of 71 consecutive cases. J. Infect. 2019, 79, 322–331. [Google Scholar] [CrossRef]
  87. Morgand, M.; Leclercq, A.; Maury, M.; Bracq-Dieye, H.; Thouvenot, P.; Vales, G.; Lecuit, M.; Charlier, C. Listeria monocytogenes-associated respiratory infections: A study of 38 consecutive cases. Clin. Microbiol. Infect. 2018, 24, 1339-e1. [Google Scholar] [CrossRef] [Green Version]
  88. Charlier, C.; Fevre, C.; Travier, L.; Cazenave, B.; Bracq-Dieye, H.; Podevin, J.; Assomany, D.; Guilbert, L.; Bossard, C.; Carpentier, F.; et al. Listeria monocytogenes-associated biliary tract infections: A study of 12 consecutive cases and review. Medicine 2014, 93, e105. [Google Scholar] [CrossRef] [PubMed]
  89. Charlier, C.; Leclercq, A.; Cazenave, B.; Desplaces, N.; Travier, L.; Cantinelli, T.; Lortholary, O.; Goulet, V.; Le Monnier, A.; Lecuit, M.; et al. Listeria monocytogenes-associated joint and bone infections: A study of 43 consecutive cases. Clin. Infect. Dis. 2012, 54, 240–248. [Google Scholar] [CrossRef] [PubMed]
  90. Wesche, A.M.; Gurtler, J.B.; Marks, B.P.; Ryser, E.T. Stress, sublethal injury, resuscitation, and virulence of bacterial foodborne pathogens. J. Food Prot. 2009, 72, 1121–1138. [Google Scholar] [CrossRef] [Green Version]
  91. Singh, S.; Shalini, R. Effect of Hurdle Technology in Food Preservation: A Review. Crit. Rev. Food Sci. Nutr. 2016, 56, 641–649. [Google Scholar] [CrossRef] [PubMed]
  92. Chorianopoulos, N.; Giaouris, E.; Grigoraki, I.; Skandamis, P.; Nychas, G.-J. Effect of acid tolerance response (ATR) on attachment of Listeria monocytogenes Scott A to stainless steel under extended exposure to acid or/and salt stress and resistance of sessile cells to subsequent strong acid challenge. Int. J. Food Microbiol. 2011, 145, 400–406. [Google Scholar] [CrossRef]
  93. Davis, M.J.; Coote, P.J.; O’Byrne, C.P. Acid tolerance in Listeria monocytogenes: The adaptive acid tolerance response (ATR) and growth-phase-dependent acid resistance. Microbiology 1996, 142, 2975–2982. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. O’Driscoll, B.; Gahan, C.G.M.; Hill, C. Adaptive acid tolerance response in Listeria monocytogenes: Isolation of an acid-tolerant mutant which demonstrates increased virulence. Appl. Environ. Microbiol. 1996, 62, 1693–1698. [Google Scholar] [CrossRef] [Green Version]
  95. Abeysundara, P.D.A.; Nannapaneni, R.; Soni, K.A.; Sharma, C.S.; Mahmoud, B. Induction and stability of oxidative stress adaptation in Listeria monocytogenes EGD (Bug600) and F1057 in sublethal concentrations of H2O2 and NaOH. Int. J. Food Microbiol. 2016, 238, 288–294. [Google Scholar] [CrossRef] [PubMed]
  96. Sibanda, T.; Buys, E.M. Modelling the survival of Listeria monocytogenes strains in soft lactic cheese following acid and salt stress exposures. Lett. Appl. Microbiol. 2019, 69, 230–236. [Google Scholar] [CrossRef] [PubMed]
  97. Skandamis, P.N.; Yoon, Y.; Stopforth, J.D.; Kendall, P.A.; Sofos, J.N. Heat and acid tolerance of Listeria monocytogenes after exposure to single and multiple sublethal stresses. Food Microbiol. 2008, 25, 294–303. [Google Scholar] [CrossRef] [PubMed]
  98. Faleiro, M.L.; Andrew, P.W.; Power, D. Stress response of Listeria monocytogenes isolated from cheese and other foods. Int. J. Food Microbiol. 2003, 84, 207–216. [Google Scholar] [CrossRef]
  99. Alvarez-Ordóñez, A.; Broussolle, V.; Colin, P.; Nguyen-The, C.; Prieto, M. The adaptive response of bacterial food-borne pathogens in the environment, host and food: Implications for food safety. Int. J. Food Microbiol. 2015, 213, 99–109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Phadtare, S. Recent developments in bacterial cold-shock response. Curr. Issues Mol. Biol. 2004, 6, 125–136. [Google Scholar] [PubMed]
  101. Roncarati, D.; Scarlato, V. Regulation of heat-shock genes in bacteria: From signal sensing to gene expression output. FEMS Microbiol. Rev. 2017, 41, 549–574. [Google Scholar] [CrossRef] [Green Version]
  102. Ryan, S.; Begley, M.; Gahan, C.G.M.; Hill, C. Molecular characterization of the arginine deiminase system in Listeria monocytogenes: Regulation and role in acid tolerance. Environ. Microbiol. 2009, 11, 432–445. [Google Scholar] [CrossRef] [PubMed]
  103. Tasara, T.; Stephan, R. Cold stress tolerance of Listeria monocytogenes: A review of molecular adaptive mechanisms and food safety implications. J. Food Prot. 2006, 69, 1473–1484. [Google Scholar] [CrossRef]
  104. Cotter, P.D.; O’Reilly, K.; Hill, C. Role of the glutamate decarboxylase acid resistance system in the survival of Listeria monocytogenes LO28 in low pH foods. J. Food Prot. 2001, 64, 1362–1368. [Google Scholar] [CrossRef] [PubMed]
  105. Bremer, E.; Krämer, R. Responses of microorganisms to osmotic stress. Annu. Rev. Microbiol. 2019, 73, 313–334. [Google Scholar] [CrossRef] [PubMed]
  106. Yan, N.; Marschner, P.; Cao, W.; Zuo, C.; Qin, W. Influence of salinity and water content on soil microorganisms. Int. Soil Water Conserv. Res. 2015, 3, 316–323. [Google Scholar] [CrossRef] [Green Version]
  107. Manzanera, M. Dealing with water stress and microbial preservation. Environ. Microbiol. 2021, 23, 3351–3359. [Google Scholar] [CrossRef]
  108. Cole, M.B.; Jones, M.V.; Holyoak, C. The effect of pH, salt concentration and temperature on the survival and growth of Listeria monocytogenes. J. Appl. Microbiol. 1990, 69, 63–72. [Google Scholar]
  109. Angelidis, A.S.; Smith, G.M. Three transporters mediate uptake of glycine betaine and carnitine by Listeria monocytogenes in response to hyperosmotic stress. Appl. Environ. Microbiol. 2003, 69, 1013–1022. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Bayles, D.O.; Wilkinson, B.J. Osmoprotectants and cryoprotectants for Listeria monocytogenes. Lett. Appl. Microbiol. 2000, 30, 23–27. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Ko, R.; Smith, L.T. Identification of an ATP-driven, osmoregulated glycine betaine transport system in Listeria monocytogenes. Appl. Environ. Microbiol. 1999, 65, 4040–4048. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Wood, J.M. Osmosensing by bacteria: Signals and membrane-based sensors. Microbiol. Mol. Biol. Rev. 1999, 63, 230–262. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Gibhardt, J.; Heidemann, J.L.; Bremenkamp, R.; Rosenberg, J.; Seifert, R.; Kaever, V.; Ficner, R.; Commichau, F.M. An extracytoplasmic protein and a moonlighting enzyme modulate synthesis of c-di-AMP in Listeria monocytogenes. Environ. Microbiol. 2020, 22, 2771–2791. [Google Scholar] [CrossRef] [Green Version]
  114. Gerhardt, P.N.; Tombras Smith, L.; Smith, G.M. Osmotic and chill activation of glycine betaine porter II in Listeria monocytogenes membrane vesicles. J. Bacteriol. 2000, 182, 2544–2550. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Sleator, R.D.; Gahan, C.G.; Abee, T.; Hill, C. Identification and disruption of betL, a secondary glycine betaine transport system linked to the salt tolerance of Listeria monocytogenes LO28. Appl. Environ. Microbiol. 1999, 65, 2078–2083. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Sleator, R.D.; Wouters, J.; Gahan, C.G.; Abee, T.; Hill, C. Analysis of the role of OpuC, an osmolyte transport system, in salt tolerance and virulence potential of Listeria monocytogenes. Appl. Environ. Microbiol. 2002, 67, 2692–2698. [Google Scholar] [CrossRef] [Green Version]
  117. Roe, A.J.; McLaggan, D.; Davidson, I.; O’Byrne, C.; Booth, I.R. Perturbation of anion balance during inhibition of growth of Escherichia coli by weak acids. J. Bacteriol. 1998, 180, 767–772. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Kim, S.A.; Rhee, M.S. Marked synergistic bactericidal effects and mode of action of medium-chain fatty acids in combination with organic acids against Escherichia coli O157:H7. Appl. Environ. Microbiol. 2013, 79, 6552–6560. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Ning, Y.; Yan, A.; Yang, K.; Wang, Z.; Li, X.; Jia, Y. Antibacterial activity of phenyllactic acid against Listeria monocytogenes and Escherichia coli by dual mechanisms. Food Chem. 2017, 228, 533–540. [Google Scholar] [CrossRef] [PubMed]
  120. Arcari, T.; Feger, M.-L.; Guerreiro, D.N.; Wu, J.; O’Byrne, C.P. Comparative review of the responses of Listeria monocytogenes and Escherichia coli to Low pH stress. Genes 2020, 11, 1330. [Google Scholar] [CrossRef]
  121. Cotter, P.D.; Ryan, S.; Gahan, C.G.M.; Hill, C. Presence of GadD1 glutamate decarboxylase in selected Listeria monocytogenes strains is associated with an ability to grow at low pH. Appl. Environ. Microbiol. 2005, 71, 2832–2839. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Spano, G.; Chieppa, G.; Beneduce, L.; Massa, S. Expression analysis of putative arcA, arcB and arcC genes partially cloned from Lactobacillus plantarum isolated from wine. J. Appl. Microbiol. 2004, 96, 185–193. [Google Scholar] [CrossRef]
  123. Ryan, S.; Hill, C.; Gahan, C.G.M. Acid stress responses in Listeria monocytogenes. In Advances in Applied Microbiology; Elsevier Masson SAS: Amsterdam, The Netherlands, 2008; pp. 67–91. [Google Scholar]
  124. Shen, Q.; Jangam, P.M.; Soni, K.A.; Nannapaneni, R.; Schilling, W.; Silva, J.L. Low, medium, and high heat tolerant strains of Listeria monocytogenes and increased heat stress resistance after exposure to sublethal heat. J. Food Prot. 2014, 77, 1298–1307. [Google Scholar] [CrossRef] [PubMed]
  125. Haykir, O.; Mohácsi-Farkas, C.; Engelhardt, T. Enhanced heat resistance of Listeria innocua as a surrogate of Listeria monocytogenes after sublethal heat treatment. Acta Aliment. 2022, 51, 241–248. [Google Scholar] [CrossRef]
  126. Lou, Y.; Yousef, A.E. Resistance of Listeria monocytogenes to heat after adaptation to environmental stresses. J. Food Prot. 1996, 59, 465–471. [Google Scholar] [CrossRef] [PubMed]
  127. Taormina, P.J.; Beuchat, L.R. Survival and heat resistance of Listeria monocytogenes after exposure to alkali and chlorine. Appl. Environ. Microbiol. 2001, 67, 2555–2563. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Van Der Veen, S.; Hain, T.; Wouters, J.A.; Hossain, H.; De Vos, W.M.; Abee, T.; Chakraborty, T.; Wells-Bennik, M.H.J. The heat-shock response of Listeria monocytogenes comprises genes involved in heat shock, cell division, cell wall synthesis, and the SOS response. Microbiology 2007, 153, 3593–3607. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  129. Hanawa, T.; Kai, M.; Kamiya, S.; Yamamoto, T. Cloning, sequencing, and transcriptional analysis of the dnaK heat shock operon of Listeria monocytogenes. Cell Stress Chaperones 2000, 5, 21–29. [Google Scholar] [CrossRef] [Green Version]
  130. Gahan, C.G.M.; O’Mahony, J.; Hill, C. Characterization of the groESL operon in Listeria monocytogenes: Utilization of two reporter systems (gfp and hly) for evaluating in vivo expression. Infect. Immun. 2001, 69, 3924–3932. [Google Scholar] [CrossRef] [Green Version]
  131. Nair, S.; Derré, I.; Msadek, T.; Gaillot, O.; Berche, P. CtsR controls class III heat shock gene expression in the human pathogen Listeria monocytogenes. Mol. Microbiol. 2000, 35, 800–811. [Google Scholar] [CrossRef] [PubMed]
  132. Cabrita, P.; Trigo, M.J.; Ferreira, R.B.; Brito, L. Differences in the expression of cold stress-related genes and in the swarming motility among persistent and sporadic strains of Listeria monocytogenes. Foodborne Pathog. Dis. 2015, 12, 576–584. [Google Scholar] [CrossRef]
  133. Bayles, D.O.; Annous, B.A.; Wilkinson, B.J. Cold stress proteins induced in Listeria monocytogenes in response to temperature downshock and growth at low temperatures. Appl. Environ. Microbiol. 1996, 62, 1116–1119. [Google Scholar] [CrossRef] [Green Version]
  134. Russell, N.J. Bacterial membranes: The effects of chill storage and food processing. An overview. Int. J. Food. Microbiol. 2002, 79, 27–34. [Google Scholar] [CrossRef]
  135. Yoon, Y.; Lee, H.; Lee, S.; Kim, S.; Choi, K.-H. Membrane fluidity-related adaptive response mechanisms of foodborne bacterial pathogens under environmental stresses. Food Res. Int. 2015, 72, 25–36. [Google Scholar] [CrossRef]
  136. Annous, B.A.; Becker, L.A.; Bayles, D.O.; Labeda, D.P.; Wilkinson, B.J. Critical role of anteiso-C15:0 fatty acid in the growth of Listeria monocytogenes at low temperatures. Appl. Environ. Microbiol. 1997, 63, 3887–3894. [Google Scholar] [CrossRef] [Green Version]
  137. Choi, K.H.; Heath, R.J.; Rock, C.O. β-ketoacyl-acyl carrier protein synthase III (FabH) is a determining factor in branched-chain fatty acid biosynthesis. J. Bacteriol. 2000, 182, 365–370. [Google Scholar] [CrossRef] [Green Version]
  138. Nelson, K.E.; Fouts, D.E.; Mongodin, E.F.; Ravel, J.; DeBoy, R.T.; Kolonay, J.F.; Rasko, D.A.; Angiuoli, S.V.; Gill, S.R.; Paulsen, I.T.; et al. Whole genome comparisons of serotype 4b and 1/2a strains of the food-borne pathogen Listeria monocytogenes reveal new insights into the core genome components of this species. Nucleic Acids Res. 2004, 32, 2386–2395. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Schmid, B.; Klumpp, J.; Raimann, E.; Loessner, M.J.; Stephan, R.; Tasara, T. Role of cold shock proteins in growth of Listeria monocytogenes under cold and osmotic stress conditions. Appl. Environ. Microbiol. 2009, 75, 1621–1627. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  140. Wemekamp-Kamphuis, H.H.; Karatzas, A.K.; Wouters, J.A.; Abee, T. Enhanced levels of cold shock proteins in Listeria monocytogenes LO28 upon exposure to low temperature and high hydrostatic pressure. Appl. Environ. Microbiol. 2002, 68, 456–463. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. Netterling, S.; Vaitkevicius, K.; Nord, S.; Johansson, J. A Listeria monocytogenes RNA helicase essential for growth and ribosomal maturation at low temperatures uses its C terminus for appropriate interaction with the ribosome. J. Bacteriol. 2012, 194, 4377–4385. [Google Scholar] [CrossRef] [Green Version]
  142. Markkula, A.; Lindstrom, M.; Johansson, P.; Bjorkroth, J.; Korkeala, H. Roles of four putative DEAD-box RNA helicase genes in growth of Listeria monocytogenes EGD-e under heat, pH, osmotic, ethanol, and oxidative stress conditions. Appl. Environ. Microbiol. 2012, 78, 6875–6882. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Bäreclev, C.; Vaitkevicius, K.; Netterling, S.; Johansson, J. DExD-box RNA-helicases in Listeria monocytogenes are important for growth, ribosomal maturation, rRNA processing and virulence factor expression. RNA Biol. 2014, 11, 1457–1466. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Mendum, M.L.; Smith, L.T. Characterization of glycine betaine porter I from Listeria monocytogenes and its roles in salt and chill tolerance. Appl. Environ. Microbiol. 2002, 68, 813–819. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Liu, S.; Graham, J.E.; Bigelow, L.; Morse, P.D.; Wilkinson, B.J. Identification of Listeria monocytogenes genes expressed in response to growth at low temperature. Appl. Environ. Microbiol. 2002, 68, 1697–1705. [Google Scholar] [CrossRef] [Green Version]
  146. Chan, Y.C.; Wiedmann, M. Physiology and genetics of Listeria monocytogenes survival and growth at cold temperatures. Crit. Rev. Food Sci. Nutr. 2008, 49, 237–253. [Google Scholar] [CrossRef]
  147. Zhao, X.; Drlica, K. Reactive oxygen species and the bacterial response to lethal stress. Curr. Opin. Microbiol. 2014, 21, 1–6. [Google Scholar] [CrossRef] [Green Version]
  148. Azizoglu, R.O.; Kathariou, S. Temperature-dependent requirement for catalase in aerobic growth of Listeria monocytogenes F2365. Appl. Environ. Microbiol. 2010, 76, 6998–7003. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  149. Suo, Y.; Huang, Y.; Liu, Y.; Shi, C.; Shi, X. The expression of superoxide dismutase (SOD) and a putative ABC transporter permease is inversely correlated during biofilm formation in Listeria monocytogenes 4b G. PLoS ONE 2012, 7, e48467. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  150. Mains, D.R.; Eallonardo, S.J.; Freitag, N.E. Identification of Listeria monocytogenes genes contributing to oxidative stress resistance under conditions relevant to host infection. Infect. Immun. 2021, 89, e00700-20. [Google Scholar] [CrossRef] [PubMed]
  151. Ruhland, B.R.; Reniere, M.L. Sense and sensor ability: Redox-responsive regulators in Listeria monocytogenes. Curr. Opin. Microbiol. 2019, 47, 20–25. [Google Scholar] [CrossRef] [PubMed]
  152. Rea, R.; Hill, C.; Gahan, C.G.M. Listeria monocytogenes PerR mutants display a small-colony phenotype, increased sensitivity to hydrogen peroxide, and significantly reduced murine virulence. Appl. Environ. Microbiol. 2005, 71, 8314–8322. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Sleator, R.D.; Watson, D.; Hill, C.; Gahan, C.G.M. The interaction between Listeria monocytogenes and the host gastrointestinal tract. Microbiology 2009, 155, 2463–2475. [Google Scholar] [CrossRef]
  154. Conte, M.P.; Petrone, G.; Di Biase, A.M.; Ammendolia, M.G.; Superti, F.; Seganti, L. Acid tolerance in Listeria monocytogenes influences invasiveness of enterocyte-like cells and macrophage-like cells. Microb. Pathog. 2000, 29, 137–144. [Google Scholar] [CrossRef]
  155. Saklani-Jusforgues, H.; Fontan, E.; Goossens, P.L. Effect of acid-adaptation on Listeria monocytogenes survival and translocation in a murine intragastric infection model. FEMS Microbiol. Lett. 2000, 193, 155–159. [Google Scholar] [CrossRef]
  156. O’Byrne, C.P.; Karatzas, K.A.G. The role of Sigma B (σB) in the stress adaptations of Listeria monocytogenes: Overlaps between stress adaptation and virulence. In Advances in Applied Microbiology; Elsevier Masson SAS: Amsterdam, The Netherlands, 2008; Volume 65, pp. 115–140. [Google Scholar]
  157. Begley, M.; Sleator, R.D.; Gahan, C.G.; Hill, C. Contribution of three bile-associated loci, bsh, pva, and btlB, to gastrointestinal persistence and bile tolerance of Listeria monocytogenes. Infect. Immun. 2005, 73, 894–904. [Google Scholar] [CrossRef] [Green Version]
  158. Sleator, R.D.; Wemekamp-Kamphuis, H.H.; Gahan, C.G.; Abee, T.; Hill, C. A PrfA-regulated bile exclusion system (BilE) is a novel virulence factor in Listeria monocytogenes. Mol. Microbiol. 2005, 55, 1183–1195. [Google Scholar] [CrossRef] [PubMed]
  159. Wiedmann, M.; Arvik, T.J.; Hurley, R.J.; Boor, K.J. General stress transcription factor σB and its role in acid tolerance and virulence of Listeria monocytogenes. J. Bacteriol. 1998, 180, 3650–3656. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  160. Sue, D.; Fink, D.; Wiedmann, M.; Boor, K.J. σB-dependent gene induction and expression in Listeria monocytogenes during osmotic and acid stress conditions simulating the intestinal environment. Microbiology 2004, 150, 3843–3855. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  161. Cetin, M.S.; Zhang, C.; Hutkins, R.W.; Benson, A.K. Regulation of transcription of compatible solute transporters by the general stress sigma factor, σB, in Listeria monocytogenes. J. Bacteriol. 2004, 186, 794–802. [Google Scholar] [CrossRef] [Green Version]
  162. Wemekamp-Kamphuis, H.H.; Wouters, J.A.; de Leeuw, P.P.; Hain, T.; Chakraborty, T.; Abee, T. Identification of sigma factor σB-controlled genes and their impact on acid stress, high hydrostatic pressure, and freeze survival in Listeria monocytogenes EGD-e. Appl. Environ. Microbiol. 2004, 70, 3457–3466. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Lee, J.H.; Choi, C.W.; Lee, T.; Kim, S.I.; Lee, J.C.; Shin, J.H. Transcription factor σB plays an important role in the production of extracellular membrane-derived vesicles in Listeria monocytogenes. PLoS ONE 2013, 8, e73196. [Google Scholar] [CrossRef] [PubMed]
  164. Mujahid, S.; Orsi, R.H.; Vangay, P.; Boor, K.J.; Wiedmann, M. Refinement of the Listeria monocytogenes σB regulon through quantitative proteomic analysis. Microbiology 2013, 159, 1109–1119. [Google Scholar] [CrossRef] [Green Version]
  165. Abram, F.; Starr, E.; Karatzas, K.A.G.; Matlawska-Wasowska, K.; Boyd, A.; Wiedmann, M.; Boor, K.J.; Connally, D.; O'Byrne, C.P. Identification of components of the sigma B regulon in Listeria monocytogenes that contribute to acid and salt tolerance. Appl. Environ. Microbiol. 2008, 74, 6848–6858. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Chaturongakul, S.; Boor, K.J. σB activation under environmental and energy stress conditions in Listeria monocytogenes. Appl. Environ. Microbiol. 2006, 72, 5197–5203. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Ferreira, A.; O’Byrne, C.P.; Boor, K.J. Role of σB in heat, ethanol, acid, and oxidative stress resistance and during carbon starvation in Listeria monocytogenes. Appl. Environ. Microbiol. 2001, 67, 4454–4457. [Google Scholar] [CrossRef] [Green Version]
  168. Garner, M.R.; Njaa, B.L.; Wiedmann, M.; Boor, K.J. Sigma B contributes to Listeria monocytogenes gastrointestinal infection but not to systemic spread in the guinea pig infection model. Infect. Immun. 2006, 74, 876–886. [Google Scholar] [CrossRef] [Green Version]
  169. Guldimann, C.; Boor, K.J.; Wiedmann, M.; Guariglia-Oropeza, V. Resilience in the face of uncertainty: Sigma factor B fine-tunes gene expression to support homeostasis in gram-positive bacteria. Appl. Environ. Microbiol. 2016, 82, 4456–4469. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  170. Dessaux, C.; Guerreiro, D.N.; Pucciarelli, M.G.; O’Byrne, C.P.; García-del Portillo, F. Impact of osmotic stress on the phosphorylation and subcellular location of Listeria monocytogenes stressosome proteins. Sci. Rep. 2020, 10, 20837. [Google Scholar] [CrossRef]
  171. Chaturongakul, S.; Boor, K.J. RsbT and RsbV contribute to σB-dependent survival under environmental, energy, and intracellular stress conditions in Listeria monocytogenes. Appl. Environ. Microbiol. 2004, 70, 5349–5356. [Google Scholar] [CrossRef] [Green Version]
  172. Freitag, N.E.; Port, G.C.; Miner, M.D. Listeria monocytogenes: From saprophyte to intracellular pathogen. Nat. Rev. Microbiol. 2009, 7, 623. [Google Scholar] [CrossRef]
  173. Freitag, N.E.; Rong, L.; Portnoy, D.A. Regulation of the prfA transcriptional activator of Listeria monocytogenes: Multiple promoter elements contribute to intracellular growth and cell-to-cell spread. Infect. Immun. 1993, 61, 2537–2544. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Gray, M.J.; Freitag, N.E.; Boor, K.J. How the bacterial pathogen Listeria monocytogenes mediates the switch from environmental Dr. Jekyll to pathogenic Mr. Hyde. Infect. Immun. 2006, 74, 2505–2512. [Google Scholar] [CrossRef] [Green Version]
  175. Miner, M.D.; Port, G.C.; Freitag, N.E. Regulation of Listeria monocytogenes virulence genes. In Listeria monocytogenes: Pathogenesis and Host Response; Goldfine, H., Shen, H., Eds.; Springer Science+Business Media, LLC: Berlin, Germany, 2007; pp. 139–158. [Google Scholar]
  176. Bruno, J.C.; Freitag, N.E. Constitutive activation of PrfA tilts the balance of Listeria monocytogenes fitness towards life within the host versus environmental survival. PLoS ONE 2010, 5, e15138. [Google Scholar] [CrossRef] [PubMed]
  177. Biswas, R.; Sonenshein, A.L.; Belitsky, B.R. Genome-wide identification of Listeria monocytogenes CodY-binding sites. Mol. Microbiol. 2020, 113, 841–858. [Google Scholar] [CrossRef]
  178. Lobel, L.; Sigal, N.; Borovok, I.; Belitsky, B.R.; Sonenshein, A.L.; Herskovits, A.A. The metabolic regulator CodY links Listeria monocytogenes metabolism to virulence by directly activating the virulence regulatory gene prfA. Mol. Microbiol. 2015, 95, 624–644. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  179. Lobel, L.; Herskovits, A.A. Systems level analyses reveal multiple regulatory activities of CodY controlling metabolism, motility and virulence in Listeria monocytogenes. PLoS Genet. 2016, 12, e1005870. [Google Scholar] [CrossRef]
  180. Lobel, L.; Sigal, N.; Borovok, I.; Ruppin, E.; Herskovits, A. Integrative genomic analysis identifies isoleucine and CodY as regulators of Listeria monocytogenes virulence. PLoS Genet. 2012, 8, e1002887. [Google Scholar] [CrossRef] [Green Version]
  181. Chico-Calero, I.; Suárez, M.; González-Zorn, B.; Scortti, M.; Slaghuis, J.; Goebel, W.; Vázquez-Boland, J.A.; European Listeria Genome Consortium. Hpt, a bacterial homolog of the microsomal glucose-6-phosphate translocase, mediates rapid intracellular proliferation in Listeria. Proc. Natl. Acad. Sci. USA 2002, 99, 431–436. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  182. Vega, Y.; Rauch, M.; Banfield, M.J.; Ermolaeva, S.; Scortti, M.; Goebel, W.; Vázquez-Boland, J.A. New Listeria monocytogenes prfA* mutants, transcriptional properties of PrfA* proteins and structure-function of the virulence regulator PrfA. Mol. Microbiol. 2004, 52, 1553–1565. [Google Scholar] [CrossRef] [PubMed]
  183. Xayarath, B.; Smart, J.I.; Mueller, K.J.; Freitag, N.E. A novel C-terminal mutation resulting in constitutive activation of the Listeria monocytogenes central virulence regulatory factor PrfA. Microbiology 2011, 157, 3138–3149. [Google Scholar] [CrossRef] [Green Version]
  184. Oropeza, V.G.; Orsi, R.H.; Guldimann, C.; Wiedmann, M.; Boor, K.J. The Listeria monocytogenes bile stimulon under acidic conditions is characterized by strain-specific patterns and the upregulation of motility, cell wall modification functions, and the PrfA regulon. Front. Microbiol. 2018, 9, 120. [Google Scholar] [CrossRef]
  185. Eshwar, A.K.; Guldimann, C.; Oevermann, A.; Tasara, T. Cold-shock domain family proteins (Csps) are involved in regulation of virulence, cellular aggregation, and flagella-based motility in Listeria monocytogenes. Front. Cell. Infect. Microbiol. 2017, 7, 453. [Google Scholar] [CrossRef]
  186. Wałecka, E.; Molenda, J.; Karpíšková, R.; Bania, J. Effect of osmotic stress and culture density on invasiveness of Listeria monocytogenes strains. Int. J. Food. Microbiol. 2011, 144, 440–445. [Google Scholar] [CrossRef] [PubMed]
  187. Kim, H.; Marquis, H.; Boor, K.J. σB contributes to Listeria monocytogenes invasion by controlling expression of inlA and inlB. Microbiology 2005, 151, 3215–3222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  188. Dussurget, O.; Cabanes, D.; Dehoux, P.; Lecuit, M.; Buchrieser, C.; Glaser, P.; Cossart, P. European Listeria Genome Consortium Listeria monocytogenes bile salt hydrolase is a PrfA-regulated virulence factor involved in the intestinal and hepatic phases of listeriosis. Mol. Microbiol. 2002, 45, 1095–1106. [Google Scholar] [PubMed]
  189. Tiensuu, T.; Andersson, C.; Rydén, P.; Johansson, J. Cycles of light and dark co-ordinate reversible colony differentiation in Listeria monocytogenes. Mol. Microbiol. 2013, 87, 909–924. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  190. Shetron-Rama, L.M.; Marquis, H.; Bouwer, H.G.A.; Freitag, N.E. Intracellular induction of Listeria monocytogenes actA expression. Infect. Immun. 2002, 70, 1087–1096. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  191. Ollinger, J.; Bowen, B.; Wiedmann, M.; Boor, K.J.; Bergholz, T.M. Listeria monocytogenes σB modulates PrfA-mediated virulence factor expression. Infect. Immun. 2009, 77, 2113–2124. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  192. Rauch, M.; Luo, Q.; Müller-Altrock, S.; Goebel, W. SigB-dependent in vitro transcription of prfA and some newly identified genes of Listeria monocytogenes whose expression is affected by PrfA in vivo. J. Bacteriol. 2005, 187, 800–804. [Google Scholar] [CrossRef] [Green Version]
  193. Lam, O.; Wheeler, J.; Tang, C.M. Thermal control of virulence factors in bacteria: A hot topic. Virulence 2014, 5, 852–862. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  194. Loh, E.; Righetti, F.; Eichner, H.; Twittenhoff, C.; Narberhaus, F. RNA thermometers in bacterial pathogens. Microbiol. Spectr. 2018, 6. [Google Scholar] [CrossRef] [PubMed]
  195. Loh, E.; Memarpour, F.; Vaitkevicius, K.; Kallipolitis, B.H.; Johansson, J.; Sondén, B. An unstructured 5′-coding region of the prfA mRNA is required for efficient translation. Nucleic Acids Res. 2012, 40, 1818–1827. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  196. Dorey, A.; Marinho, C.; Piveteau, P.; O’byrne, C. Role and regulation of the stress activated sigma factor sigma B (σB) in the saprophytic and host-associated life stages of Listeria monocytogenes. In Advances in Applied Microbiology, 1st ed.; Gadd, G.M., Sariaslani, S., Eds.; Elsevier Inc.: Amsterdam, The Netherlands, 2019; pp. 1–48. [Google Scholar]
  197. Bennett, H.J.; Pearce, D.M.; Glenn, S.; Taylor, C.M.; Kuhn, M.; Sonenshein, A.L.; Andrew, P.W.; Roberts, I.S. Characterization of relA and codY mutants of Listeria monocytogenes: Identification of the CodY regulon and its role in virulence. Mol. Microbiol. 2007, 63, 1453–1467. [Google Scholar] [CrossRef] [PubMed]
  198. Reniere, M.; Whiteley, A.; Hamilton, K.L.; John, S.M.; Lauer, P.; Brennan, R.; Portnoy, D.A. Glutathione activates virulence gene expression of an intracellular pathogen. Nature 2015, 517, 170–173. [Google Scholar] [CrossRef] [Green Version]
  199. Hall, M.; Grundström, C.; Begum, A.; Lindberg, M.J.; Sauer, U.H.; Almqvist, F.; Johansson, J.; Sauer-Eriksson, A.E. Structural basis for glutathione-mediated activation of the virulence regulatory protein PrfA in Listeria. Proc. Natl. Acad. Sci. USA 2016, 113, 14733–14738. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  200. Gopal, S.; Borovok, I.; Ofer, A.; Yanku, M.; Cohen, G.; Goebel, W.; Kreft, J.; Aharonowitz, Y. A multidomain fusion protein in Listeria monocytogenes catalyzes the two primary activities for glutathione biosynthesis. J. Bacteriol. 2005, 187, 3839–3847. [Google Scholar] [CrossRef] [Green Version]
  201. Schärer, K.; Stephan, R.; Tasara, T. Cold shock proteins contribute to the regulation of listeriolysin O production in Listeria monocytogenes. Foodborne Pathog. Dis. 2013, 10, 1023–1029. [Google Scholar] [CrossRef] [Green Version]
  202. Cheng, Y.; Siletzky, R.M.; Kathariou, S. Genomic Divisions/Lineages, Epidemic Clones, and Population Structure. In Handbook of Listeria monocytogenes; Liu, D., Ed.; CRC Press: Boca Raton, FL, USA, 2008; pp. 337–358. [Google Scholar]
  203. Orsi, R.H.; den Bakker, H.C.; Wiedmann, M. Listeria monocytogenes lineages: Genomics, evolution, ecology, and phenotypic characteristics. Int. J. Med. Microbiol. 2011, 301, 79–96. [Google Scholar] [CrossRef] [PubMed]
  204. Moura, A.; Criscuolo, A.; Pouseele, H.; Maury, M.M.; Leclercq, A.; Tarr, C.; Björkman, J.T.; Dallman, T.; Reimer, A.; Enouf, V.; et al. Whole genome-based population biology and epidemiological surveillance of Listeria monocytogenes. Nat. Microbiol. 2016, 2, 16185. [Google Scholar] [CrossRef] [PubMed]
  205. Haase, J.K.; Didelot, X.; Lecuit, M.; Korkeala, H. L. monocytogenes MSLT Study Group; Achtman, M. The ubiquitous nature of Listeria monocytogenes clones: A large-scale Multilocus Sequence Typing study. Environ. Microbiol. 2014, 16, 405–416. [Google Scholar] [CrossRef]
  206. Doijad, S.; Weigel, M.; Barbuddhe, S.; Blom, J.; Goesmann, A.; Hain, T.; Chakraborty, T. Phylogenomic grouping of Listeria monocytogenes. Can. J. Microbiol. 2015, 61, 637–646. [Google Scholar] [CrossRef]
  207. Schiavano, G.F.; Ateba, C.N.; Petruzzelli, A.; Mele, V.; Amagliani, G.; Guidi, F.; De Santi, M.; Pomilio, F.; Blasi, G.; Gattuso, A.; et al. Whole-genome sequencing characterization of virulence profiles of Listeria monocytogenes food and human isolates and in vitro adhesion/invasion assessment. Microorganisms 2022, 10, 62. [Google Scholar] [CrossRef] [PubMed]
  208. Deng, X.; Phillippy, A.M.; Li, Z.; Salzberg, S.L.; Zhang, W. Probing the pan-genome of Listeria monocytogenes: New insights into intraspecific niche expansion and genomic diversification. BMC Genom. 2010, 11, 500. [Google Scholar] [CrossRef] [Green Version]
  209. Maury, M.M.; Tsai, Y.H.; Charlier, C.; Touchon, M.; Chenal-Francisque, V.; Leclercq, A.; Criscuolo, A.; Gaultier, C.; Roussel, S.; Brisabois, A.; et al. Uncovering Listeria monocytogenes hypervirulence by harnessing its biodiversity. Nat Genet. 2016, 48, 308. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  210. Vázquez-Boland, J.A.; Wagner, M.; Scortti, M. Why are some Listeria monocytogenes genotypes more likely to cause invasive (brain, placental) infection? mBio 2020, 11, e03126-20. [Google Scholar] [CrossRef]
  211. Lee, S.; Chen, Y.; Gorski, L.; Ward, T.J.; Osborne, J.; Kathariou, S. Listeria monocytogenes source distribution analysis indicates regional heterogeneity and ecological niche preference among serotype 4b clones. mBio 2018, 9, e00396-18. [Google Scholar] [CrossRef] [Green Version]
  212. da Silva, M.F.; Ferreira, V.; Magalhães, R.; Almeida, G.; Alves, A.; Teixeira, P. Detection of premature stop codons leading to truncated internalin A among food and clinical strains of Listeria monocytogenes. Food Microbiol. 2017, 63, 6–11. [Google Scholar] [CrossRef]
  213. Nightingale, K.K.; Ivy, R.A.; Ho, A.J.; Fortes, E.D.; Njaa, B.L.; Peters, R.M.; Wiedmann, M. inlA premature stop codons are common among Listeria monocytogenes isolates from foods and yield virulence-attenuated strains that confer protection against fully virulent strains. Appl. Environ. Microbiol. 2008, 74, 6570–6583. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  214. Van Stelten, A.; Simpson, J.M.; Ward, T.J.; Nightingale, K.K. Revelation by single-nucleotide polymorphism genotyping that mutations leading to a premature stop codon in inlA are common among Listeria monocytogenes isolates from ready-to-eat foods but not human listeriosis cases. Appl. Environ. Microbiol. 2010, 76, 2783–2790. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  215. Cotter, P.D.; Draper, L.A.; Lawton, E.M.; Daly, K.M.; Groeger, D.S.; Casey, P.G.; Ross, R.P.; Hill, C. Listeriolysin S, a novel peptide haemolysin associated with a subset of lineage I Listeria monocytogenes. PLoS Pathog. 2008, 4, e1000144. [Google Scholar] [CrossRef] [Green Version]
  216. Quereda, J.J.; Meza-Torres, J.; Cossart, P.; Pizarro-Cerdá, J. Listeriolysin S: A bacteriocin from epidemic Listeria monocytogenes strains that targets the gut microbiota. Gut Microbes 2017, 8, 384–391. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  217. Bergholz, T.M.; den Bakker, H.C.; Fortes, E.D.; Boor, K.J.; Wiedmann, M. Salt stress phenotypes in Listeria monocytogenes vary by genetic lineage and temperature. Foodborne Pathog. Dis. 2010, 7, 1537–1549. [Google Scholar] [CrossRef] [PubMed]
  218. Horlbog, J.A.; Kent, D.; Stephan, R.; Guldimann, C. Surviving host- and food relevant stresses: Phenotype of L. monocytogenes strains isolated from food and clinical sources. Nat. Sci. Rep. 2018, 8, 12931. [Google Scholar] [CrossRef]
  219. Pirone-Davies, C.; Chen, Y.; Pightling, A.; Ryan, G.; Wang, Y.; Yao, K.; Hoffmann, M.; Allard, M.W. Genes significantly associated with lineage II food isolates of Listeria monocytogenes. BMC Genom. 2018, 19, 708. [Google Scholar] [CrossRef]
  220. Naditz, A.L.; Dzieciol, M.; Wagner, M.; Schmitz-Esser, S. Plasmids contribute to food processing environment–associated stress survival in three Listeria monocytogenes ST121, ST8, and ST5 strains. Int. J. Food Microbiol. 2019, 299, 39–46. [Google Scholar] [CrossRef] [Green Version]
  221. Korsak, D.; Chmielowska, C.; Szuplewska, M.; Bartosik, D. Prevalence of plasmid-borne benzalkonium chloride resistance cassette bcrABC and cadmium resistance cadA genes in nonpathogenic Listeria spp. isolated from food and food-processing environments. Int. J. Food Microbiol. 2019, 290, 247–253. [Google Scholar] [CrossRef] [PubMed]
  222. Gelbicova, T.; Florianova, M.; Hluchanova, L.; Kalova, A.; Korena, K.; Strakova, N.; Karpiskova, R. Comparative analysis of genetic determinants encoding cadmium, arsenic, and benzalkonium chloride resistance in Listeria monocytogenes of human, food, and environmental origin. Front. Microbiol. 2021, 11, 599882. [Google Scholar] [CrossRef]
  223. Cerutti, F.; Mallet, L.; Painset, A.; Hoede, C.; Moisan, A.; Bécavin, C.; Duval, M.; Dussurget, O.; Cossart, P.; Gaspin, C.; et al. Unraveling the evolution and coevolution of small regulatory RNAs and coding genes in Listeria. BMC Genom. 2017, 18, 882. [Google Scholar] [CrossRef] [Green Version]
Figure 1. Schematic representation of the infection cycle of L. monocytogenes in humans. Following ingestion of contaminated food, the bacteria invade the intestinal barrier into the bloodstream. Through the portal circulation, the organism is transported to the liver and spleen where it multiplies before being disseminated into the bloodstream. The organism subsequently infects the brain and the placenta/fetus in pregnant women. The schematic art pieces were obtained from Servier Medical art ( (accessed on 1 March 2022)). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.
Figure 1. Schematic representation of the infection cycle of L. monocytogenes in humans. Following ingestion of contaminated food, the bacteria invade the intestinal barrier into the bloodstream. Through the portal circulation, the organism is transported to the liver and spleen where it multiplies before being disseminated into the bloodstream. The organism subsequently infects the brain and the placenta/fetus in pregnant women. The schematic art pieces were obtained from Servier Medical art ( (accessed on 1 March 2022)). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.
Microorganisms 10 01522 g001
Figure 2. Pathways of the L. monocytogenes invasion of the intestinal barrier. In the InlA-mediated transcytosis (A), bacterial cells are taken into the enterocytes by endocytosis through the interaction of InlA and any exposed E-cadherin receptors followed by subsequent exocytosis into the lamina propria. In the LAP-mediated translocation (B), the interaction between the bacterial surface protein LAP and the receptor Hsp60 causes an opening of tight junctions facilitating the movement of bacterial cells into the lamina propria. In the M-cell-mediated pathway (C), bacterial cells are passively taken in by M-cells and released by exocytosis into the lamina propria. The schematic art pieces were obtained from Servier Medical art ( Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.
Figure 2. Pathways of the L. monocytogenes invasion of the intestinal barrier. In the InlA-mediated transcytosis (A), bacterial cells are taken into the enterocytes by endocytosis through the interaction of InlA and any exposed E-cadherin receptors followed by subsequent exocytosis into the lamina propria. In the LAP-mediated translocation (B), the interaction between the bacterial surface protein LAP and the receptor Hsp60 causes an opening of tight junctions facilitating the movement of bacterial cells into the lamina propria. In the M-cell-mediated pathway (C), bacterial cells are passively taken in by M-cells and released by exocytosis into the lamina propria. The schematic art pieces were obtained from Servier Medical art ( Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.
Microorganisms 10 01522 g002
Figure 3. L. monocytogenes invasion of target cells and cell-to-cell spread. The bacterial surface internalins InlA and InlB interaction with their respective cell surface receptors result in the internalization of bacterial cells. The primary endocytic vacuole is then lysed through the activity of LLO and PI-PLC. Following a period of replication in the cytosol, the release of ActA stimulates actin polymerization by recruiting host nucleation proteins VASP and Arp2/3 complex. The formation of comet tails propels the bacterial cells and enables them to spread to neighboring cells through membrane protrusions. Lysis of the double membrane of the secondary vacuole by the action of LLO and PC-PLC causes the release of bacterial cells into the cytosol.
Figure 3. L. monocytogenes invasion of target cells and cell-to-cell spread. The bacterial surface internalins InlA and InlB interaction with their respective cell surface receptors result in the internalization of bacterial cells. The primary endocytic vacuole is then lysed through the activity of LLO and PI-PLC. Following a period of replication in the cytosol, the release of ActA stimulates actin polymerization by recruiting host nucleation proteins VASP and Arp2/3 complex. The formation of comet tails propels the bacterial cells and enables them to spread to neighboring cells through membrane protrusions. Lysis of the double membrane of the secondary vacuole by the action of LLO and PC-PLC causes the release of bacterial cells into the cytosol.
Microorganisms 10 01522 g003
Figure 4. Mechanism of Rsb-mediated regulation of SigB expression and activity in L. monocytogenes.
Figure 4. Mechanism of Rsb-mediated regulation of SigB expression and activity in L. monocytogenes.
Microorganisms 10 01522 g004
Figure 5. An illustration of the overlap and interactions between SigB and PrfA in L. monocytogenes. Solid arrows indicate positive regulation. The dotted arrow indicates negative regulation.
Figure 5. An illustration of the overlap and interactions between SigB and PrfA in L. monocytogenes. Solid arrows indicate positive regulation. The dotted arrow indicates negative regulation.
Microorganisms 10 01522 g005
Table 1. Stress response proteins and virulence factors expressed by L. monocytogenes at different stages of the infection cycle.
Table 1. Stress response proteins and virulence factors expressed by L. monocytogenes at different stages of the infection cycle.
Stage of Infection CycleStress Response Proteins/Virulence FactorFunctionTranscriptional RegulatorReferences
Intestinal phaseGadD2T2Glutamate decarboxylase for survival of stomach aciditySigB[104]
OpuCCarnitine transporter for osmotic stress survivalSigB[116]
BshBile salt hydrolase for bile stress survivalSigB and PrfA[157,184]
BilEBile exclusion system for bile stress survivalSigB and PrfA[158]
InlAAdhesion and invasion of enterocytesSigB and PrfA[39,168]
InlBAdhesion and invasion of enterocytesSigB and PrfA[39]
ActABacterial aggregation and intestinal colonizationSigB and PrfA[26,189]
Intracellular phaseLLOPrimary vacuole lysisPrfA[46]
PI-PLCPrimary vacuole lysisPrfA[53]
PC-PLCSecondary vacuole lysisPrfA[54]
ActAIntracellular motility and cell-to-cell spreadPrfA[56,190]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Sibanda, T.; Buys, E.M. Listeria monocytogenes Pathogenesis: The Role of Stress Adaptation. Microorganisms 2022, 10, 1522.

AMA Style

Sibanda T, Buys EM. Listeria monocytogenes Pathogenesis: The Role of Stress Adaptation. Microorganisms. 2022; 10(8):1522.

Chicago/Turabian Style

Sibanda, Thulani, and Elna M. Buys. 2022. "Listeria monocytogenes Pathogenesis: The Role of Stress Adaptation" Microorganisms 10, no. 8: 1522.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop