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Topical Collection "Staphylococcus aureus Toxins"

A topical collection in Toxins (ISSN 2072-6651). This collection belongs to the section "Bacterial Toxins".

Editor

Collection Editor
Prof. Dr. Yinduo Ji

Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA
Website | E-Mail
Phone: +1-612-624-2757
Fax: +1-612-625-5203
Interests: Staphylococcus aureus; MRSA; two-component regulatory systems; toxins; essential proteins; gene regulation; antibacterial drug discovery; host pathogen interactions

Topical Collection Information

Dear Colleagues,

Staphylococcus aureus is a major pathogen that causes a variety of infections, including commonly superficial skin and soft tissue infections and severe systematic infections. The ability of this organism to cause significant illness is mainly due to its production of numerous toxins, such as α-, β-, γ-, and δ-toxins, Panton-Valentine leukocidin, Phenol soluble modulins (PSM), enterotoxins, and toxic shock syndrome toxin-1. It has been revealed that these toxins are able to bind to distinct receptors and trigger various signaling pathways and lead to inflammatory responses and cell death during host-cell pathogen interactions. This Special Issue of Toxins will cover reviews and research articles on the advancements in the field of cellular and molecular pathogenesis of staphylococcal toxins, toxoid vaccine development, and regulatory mechanism of toxin production. Animal models used for validation the pathogenicity of staphylococcal toxins will also be covered in this Special Issue.

Prof. Dr. Yinduo Ji
Collection Editor

Submission

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1200 CHF (Swiss Francs).

Keywords

  • toxin
  • hemolycin
  • leukotoxin
  • enterotoxin
  • superantigen
  • signaling pathway
  • cytotoxicity
  • gene regulation
  • toxoid
  • vaccine

Published Papers (20 papers)

2017

Jump to: 2016, 2015

Open AccessArticle Epidermal Growth Factor Receptor Signaling Enhances the Proinflammatory Effects of Staphylococcus aureus Gamma-Toxin on the Mucosa
Toxins 2017, 9(7), 202; doi:10.3390/toxins9070202
Received: 19 May 2016 / Revised: 2 June 2017 / Accepted: 9 June 2017 / Published: 28 June 2017
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Abstract
Staphylococcus aureus (S. aureus) produces many different exotoxins including the gamma-toxins, HlgAB and HlgCB. Gamma-toxins form pores in both leukocyte and erythrocyte membranes, resulting in cell lysis. The genes encoding gamma-toxins are present in most strains of S. aureus, and are
[...] Read more.
Staphylococcus aureus (S. aureus) produces many different exotoxins including the gamma-toxins, HlgAB and HlgCB. Gamma-toxins form pores in both leukocyte and erythrocyte membranes, resulting in cell lysis. The genes encoding gamma-toxins are present in most strains of S. aureus, and are commonly expressed in clinical isolates recovered from menstrual Toxic Shock Syndrome (mTSS) patients. This study set out to investigate the cytotoxic and proinflammatory effects of gamma-toxins on vaginal epithelial surfaces. We found that both HlgAB and HlgCB were cytotoxic to cultured human vaginal epithelial cells (HVECs) and induced cytokine production at sub-cytotoxic doses. Cytokine production induced by gamma-toxin treatment of HVECs was found to involve epidermal growth factor receptor (EGFR) signaling and mediated by shedding of EGFR ligands from the cell surface. The gamma-toxin subunits displayed differential binding to HVECs (HlgA 93%, HlgB 97% and HlgC 28%) with both components (HlgAB or HlgCB) required for maximum detectable binding and significant stimulation of cytokine production. In studies using full thickness ex vivo porcine vaginal mucosa, HlgAB or HlgCB stimulated a dose-dependent cytokine response, which was reduced significantly by inhibition of EGFR signaling. The effects of gamma-toxins on porcine vaginal tissue and cultured HVECs were validated using ex vivo human ectocervical tissue. Collectively, these studies have identified the EGFR-signaling pathway as a key component in gamma-toxin-induced proinflammatory changes at epithelial surfaces and highlight a potential therapeutic target to diminish toxigenic effects of S. aureus infections. Full article
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Open AccessArticle Virulence Genes of S. aureus from Dairy Cow Mastitis and Contagiousness Risk
Toxins 2017, 9(6), 195; doi:10.3390/toxins9060195
Received: 25 May 2017 / Revised: 16 June 2017 / Accepted: 19 June 2017 / Published: 21 June 2017
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Abstract
Staphylococcus aureus (S. aureus) is a major agent of dairy cow intramammary infections: the different prevalences of mastitis reported might be related to a combination of S. aureus virulence factors beyond host factors. The present study considered 169 isolates from different
[...] Read more.
Staphylococcus aureus (S. aureus) is a major agent of dairy cow intramammary infections: the different prevalences of mastitis reported might be related to a combination of S. aureus virulence factors beyond host factors. The present study considered 169 isolates from different Italian dairy herds that were classified into four groups based on the prevalence of S. aureus infection at the first testing: low prevalence (LP), medium–low (MLP), medium–high (MHP) and high (HP). We aimed to correlate the presence of virulence genes with the prevalence of intramammary infections in order to develop new strategies for the control of S. aureus mastitis. Microarray data were statistically evaluated using binary logistic regression and correspondence analysis to screen the risk factors and the relationship between prevalence group and gene. The analysis showed: (1) 24 genes at significant risk of being detected in all the herds with infection prevalence >5%, including genes belonging to microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), immune evasion and serine proteases; and (2) a significant correlation coefficient between the genes interacting with the host immune response and HP isolates against LP ones. These results support the hypothesis that virulence factors, in addition to cow management, could be related to strain contagiousness, offering new insights into vaccine development. Full article
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Open AccessArticle Molecular Epidemiology of Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus in the Ovine Dairy Chain and in Farm-Related Humans
Toxins 2017, 9(5), 161; doi:10.3390/toxins9050161
Received: 17 March 2017 / Revised: 5 May 2017 / Accepted: 9 May 2017 / Published: 16 May 2017
PDF Full-text (443 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Staphylococcus aureus is a major cause of clinical infections in humans and its enterotoxins cause foodborne disease. In the present study, we tested a total of 51 isolates of S. aureus from small-ruminant dairy farms with artisan dairy facilities, all located in Latium,
[...] Read more.
Staphylococcus aureus is a major cause of clinical infections in humans and its enterotoxins cause foodborne disease. In the present study, we tested a total of 51 isolates of S. aureus from small-ruminant dairy farms with artisan dairy facilities, all located in Latium, Italy. The farms have a known history of a high prevalence of methicillin-resistant S. aureus (MRSA). Most of the MRSA isolates (27 of 51) belonged to spa-type t127 (43.1%), followed by t2678 (3.9%), t044 (2%), t1166 (2%), and t1773 (2%). PFGE performed on mecA positive strains identified one cluster (≥ 80% of similarity), comprising 22 MRSA. Nine of twenty-two MRSA isolates were assigned human host origin, and 13 isolates did not belong to a specific host. During the characterization study, one strain isolated from bulk tank milk samples harbored the pvl gene; the strain was not enterotoxigenic with a non-specific host according to the biotyping scheme, highlighting the possible emerging risk of transmission of bacterial virulence factors by foods, the environment, and foodhandlers. These findings stress the importance of hygienic measures at all processing steps of the food production chain and underline that monitoring for the presence of MRSA throughout the food chain is essential for public health. Full article
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Open AccessArticle Human scFvs That Counteract Bioactivities of Staphylococcus aureus TSST-1
Toxins 2017, 9(2), 50; doi:10.3390/toxins9020050
Received: 7 November 2016 / Accepted: 9 February 2017 / Published: 17 February 2017
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Abstract
Some Staphylococcus aureus isolates produced toxic shock syndrome toxin-1 (TSST-1) which is a pyrogenic toxin superantigen (PTSAg). The toxin activates a large fraction of peripheral blood T lymphocytes causing the cells to proliferate and release massive amounts of pro-inflammatory cytokines leading to a
[...] Read more.
Some Staphylococcus aureus isolates produced toxic shock syndrome toxin-1 (TSST-1) which is a pyrogenic toxin superantigen (PTSAg). The toxin activates a large fraction of peripheral blood T lymphocytes causing the cells to proliferate and release massive amounts of pro-inflammatory cytokines leading to a life-threatening multisystem disorder: toxic shock syndrome (TSS). PTSAg-mediated-T cell stimulation circumvents the conventional antigenic peptide presentation to T cell receptor (TCR) by the antigen-presenting cell (APC). Instead, intact PTSAg binds directly to MHC-II molecule outside peptide binding cleft and simultaneously cross-links TCR-Vβ region. Currently, there is neither specific TSS treatment nor drug that directly inactivates TSST-1. In this study, human single chain antibodies (HuscFvs) that bound to and neutralized bioactivities of the TSST-1 were generated using phage display technology. Three E. coli clones transfected with TSST-1-bound phages fished-out from the human scFv library using recombinant TSST-1 as bait expressed TSST-1-bound-HuscFvs that inhibited the TSST-1-mediated T cell activation and pro-inflammatory cytokine gene expressions and productions.Computerized simulation, verified by mutations of the residues of HuscFv complementarity determining regions (CDRs),predicted to involve in target binding indicated that the HuscFvs formed interface contact with the toxin residues important for immunopathogenesis. The HuscFvs have high potential for future therapeutic application. Full article
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Open AccessArticle Above and beyond C5a Receptor Targeting by Staphylococcal Leucotoxins: Retrograde Transport of Panton–Valentine Leucocidin and γ-Hemolysin
Toxins 2017, 9(1), 41; doi:10.3390/toxins9010041
Received: 16 November 2016 / Revised: 10 January 2017 / Accepted: 16 January 2017 / Published: 20 January 2017
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Abstract
Various membrane receptors associated with the innate immune response have recently been identified as mediators of the cellular action of Staphylococcus aureus leucotoxins. Two of these, the Panton–Valentine leucotoxin LukS-PV/LukF-PV and the γ-hemolysin HlgC/HlgB, bind the C5a complement-derived peptide receptor. These leucotoxins utilize
[...] Read more.
Various membrane receptors associated with the innate immune response have recently been identified as mediators of the cellular action of Staphylococcus aureus leucotoxins. Two of these, the Panton–Valentine leucotoxin LukS-PV/LukF-PV and the γ-hemolysin HlgC/HlgB, bind the C5a complement-derived peptide receptor. These leucotoxins utilize the receptor to induce intracellular Ca2+ release from internal stores, other than those activated by C5a. The two leucotoxins are internalized with the phosphorylated receptor, but it is unknown whether they divert retrograde transport of the receptor or follow another pathway. Immunolabeling and confocal microscopic techniques were used to analyze the presence of leucotoxins in endosomes, lysosomes, endoplasmic reticulum, and Golgi. The two leucotoxins apparently followed retrograde transport similar to that of the C5a peptide-activated receptor. However, HlgC/HlgB reached the Golgi network very early, whereas LukS-PV/LukF-PV followed slower kinetics. The HlgC/HlgB leucotoxin remained in neutrophils 6 h after a 10-min incubation of the cells in the presence of the toxin with no signs of apoptosis, whereas apoptosis was observed 3 h after neutrophils were incubated with LukS-PV/LukF-PV. Such retrograde transport of leucotoxins provides a novel understanding of the cellular effects initiated by sublytic concentrations of these toxins. Full article
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2016

Jump to: 2017, 2015

Open AccessArticle ATP Release from Human Airway Epithelial Cells Exposed to Staphylococcus aureus Alpha-Toxin
Toxins 2016, 8(12), 365; doi:10.3390/toxins8120365
Received: 6 January 2016 / Revised: 30 November 2016 / Accepted: 1 December 2016 / Published: 6 December 2016
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Abstract
Airway epithelial cells reduce cytosolic ATP content in response to treatment with S. aureus alpha-toxin (hemolysin A, Hla). This study was undertaken to investigate whether this is due to attenuated ATP generation or to release of ATP from the cytosol and extracellular ATP
[...] Read more.
Airway epithelial cells reduce cytosolic ATP content in response to treatment with S. aureus alpha-toxin (hemolysin A, Hla). This study was undertaken to investigate whether this is due to attenuated ATP generation or to release of ATP from the cytosol and extracellular ATP degradation by ecto-enzymes. Exposure of cells to rHla did result in mitochondrial calcium uptake and a moderate decline in mitochondrial membrane potential, indicating that ATP regeneration may have been attenuated. In addition, ATP may have left the cells through transmembrane pores formed by the toxin or through endogenous release channels (e.g., pannexins) activated by cellular stress imposed on the cells by toxin exposure. Exposure of cells to an alpha-toxin mutant (H35L), which attaches to the host cell membrane but does not form transmembrane pores, did not induce ATP release from the cells. The Hla-mediated ATP-release was completely blocked by IB201, a cyclodextrin-inhibitor of the alpha-toxin pore, but was not at all affected by inhibitors of pannexin channels. These results indicate that, while exposure of cells to rHla may somewhat reduce ATP production and cellular ATP content, a portion of the remaining ATP is released to the extracellular space and degraded by ecto-enzymes. The release of ATP from the cells may occur directly through the transmembrane pores formed by alpha-toxin. Full article
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Open AccessArticle Enterotoxin Gene Cluster-Encoded SEI and SElN from Staphylococcus aureus Isolates are Crucial for the Induction of Human Blood Cell Proliferation and Pathogenicity in Rabbits
Toxins 2016, 8(11), 314; doi:10.3390/toxins8110314
Received: 1 September 2016 / Revised: 20 October 2016 / Accepted: 25 October 2016 / Published: 28 October 2016
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Abstract
Among the toxin family of bacterial superantigens, the six members of the enterotoxin gene cluster (egc) seem to have unusual characteristics. They are present in the majority of Staphylococcus aureus strains, but their role in disease remains uncertain. We assessed secretion levels, immunogenicity,
[...] Read more.
Among the toxin family of bacterial superantigens, the six members of the enterotoxin gene cluster (egc) seem to have unusual characteristics. They are present in the majority of Staphylococcus aureus strains, but their role in disease remains uncertain. We assessed secretion levels, immunogenicity, and toxicity of native and recombinant egc proteins. After having developed enzyme-linked immunosorbent assays, we found different quantities of egc proteins secreted by bacterial isolates. Supernatants induced proliferation of human peripheral blood mononuclear cells. However, purified recombinant egc proteins were shown to have differing superantigenicity potentials. Immunization with identical amounts of all members of egc, and the prominent toxic agent SEB, resulted in neutralizing antisera. Two egc proteins, SEI and SElN, were found to play a predominant role within the cluster. Both displayed the highest potential to activate blood cells, and were essential to be neutralized in supernatants. The application of a supernatant of a strain bearing only egc was sufficient for a lethal outcome in a rabbit model. Again, neutralization of SEI and SElN led to the survival of all tested animals. Finally, nanogram amounts of purified rSEI and rSElN led to lethality in vivo, pointing out the importance of both as virulence determinants among egc superantigens. Full article
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Open AccessReview Staphylococcus aureus Toxins and Diabetic Foot Ulcers: Role in Pathogenesis and Interest in Diagnosis
Toxins 2016, 8(7), 209; doi:10.3390/toxins8070209
Received: 14 May 2016 / Revised: 29 June 2016 / Accepted: 1 July 2016 / Published: 7 July 2016
Cited by 3 | PDF Full-text (1356 KB) | HTML Full-text | XML Full-text
Abstract
Infection of foot ulcers is a common, often severe and costly complication in diabetes. Diabetic foot infections (DFI) are mainly polymicrobial, and Staphylococcus aureus is the most frequent pathogen isolated. The numerous virulence factors and toxins produced by S. aureus during an infection
[...] Read more.
Infection of foot ulcers is a common, often severe and costly complication in diabetes. Diabetic foot infections (DFI) are mainly polymicrobial, and Staphylococcus aureus is the most frequent pathogen isolated. The numerous virulence factors and toxins produced by S. aureus during an infection are well characterized. However, some particular features could be observed in DFI. The aim of this review is to describe the role of S. aureus in DFI and the implication of its toxins in the establishment of the infection. Studies on this issue have helped to distinguish two S. aureus populations in DFI: toxinogenic S. aureus strains (harboring exfoliatin-, EDIN-, PVL- or TSST-encoding genes) and non-toxinogenic strains. Toxinogenic strains are often present in infections with a more severe grade and systemic impact, whereas non-toxinogenic strains seem to remain localized in deep structures and bone involving diabetic foot osteomyelitis. Testing the virulence profile of bacteria seems to be a promising way to predict the behavior of S. aureus in the chronic wounds. Full article
Open AccessArticle Biofilm-Forming Methicillin-Resistant Staphylococcus aureus Survive in Kupffer Cells and Exhibit High Virulence in Mice
Toxins 2016, 8(7), 198; doi:10.3390/toxins8070198
Received: 28 March 2016 / Revised: 15 June 2016 / Accepted: 24 June 2016 / Published: 30 June 2016
Cited by 2 | PDF Full-text (9212 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Although Staphylococcus aureus is part of the normal body flora, heavy usage of antibiotics has resulted in the emergence of methicillin-resistant strains (MRSA). MRSA can form biofilms and cause indwelling foreign body infections, bacteremia, soft tissue infections, endocarditis, and osteomyelitis. Using an in
[...] Read more.
Although Staphylococcus aureus is part of the normal body flora, heavy usage of antibiotics has resulted in the emergence of methicillin-resistant strains (MRSA). MRSA can form biofilms and cause indwelling foreign body infections, bacteremia, soft tissue infections, endocarditis, and osteomyelitis. Using an in vitro assay, we screened 173 clinical blood isolates of MRSA and selected 20 high-biofilm formers (H-BF) and low-biofilm formers (L-BF). These were intravenously administered to mice and the general condition of mice, the distribution of bacteria, and biofilm in the liver, lung, spleen, and kidney were investigated. MRSA count was the highest in the liver, especially within Kupffer cells, which were positive for acid polysaccharides that are associated with intracellular biofilm. After 24 h, the general condition of the mice worsened significantly in the H-BF group. In the liver, bacterial deposition and aggregation and the biofilm-forming spot number were all significantly greater for H-BF group than for L-BF. CFU analysis revealed that bacteria in the H-BF group survived for long periods in the liver. These results indicate that the biofilm-forming ability of MRSA is a crucial factor for intracellular persistence, which could lead to chronic infections. Full article
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Open AccessReview A Review of the Methods for Detection of Staphylococcus aureus Enterotoxins
Toxins 2016, 8(7), 176; doi:10.3390/toxins8070176
Received: 17 March 2016 / Accepted: 30 May 2016 / Published: 24 June 2016
Cited by 4 | PDF Full-text (1491 KB) | HTML Full-text | XML Full-text
Abstract
Food safety has attracted extensive attention around the world, and food-borne diseases have become one of the major threats to health. Staphylococcus aureus is a major food-borne pathogen worldwide and a frequent contaminant of foodstuffs. Staphylococcal enterotoxins (SEs) produced by some S. aureus
[...] Read more.
Food safety has attracted extensive attention around the world, and food-borne diseases have become one of the major threats to health. Staphylococcus aureus is a major food-borne pathogen worldwide and a frequent contaminant of foodstuffs. Staphylococcal enterotoxins (SEs) produced by some S. aureus strains will lead to staphylococcal food poisoning (SFP) outbreaks. The most common symptoms caused by ingestion of SEs within food are nausea, vomiting, diarrhea and cramps. Children will suffer SFP by ingesting as little as 100 ng of SEs, and only a few micrograms of SEs are enough to cause SPF in vulnerable populations. Therefore, it is a great challenge and of urgent need to detect and identify SEs rapidly and accurately for governmental and non-governmental agencies, including the military, public health departments, and health care facilities. Herein, an overview of SE detection has been provided through a comprehensive literature survey. Full article
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Open AccessArticle Transcytosis, Antitumor Activity and Toxicity of Staphylococcal Enterotoxin C2 as an Oral Administration Protein Drug
Toxins 2016, 8(6), 185; doi:10.3390/toxins8060185
Received: 19 March 2016 / Accepted: 6 June 2016 / Published: 16 June 2016
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Abstract
Staphylococcal enterotoxin C2 (SEC2) is a classical superantigen (SAg), which can tremendously activate T lymphocytes at very low dosage, thus exerting its powerful antitumor activity. As an intravenous protein drug and a bacterial toxin, SEC2 has some limitations including poor patient compliance and
[...] Read more.
Staphylococcal enterotoxin C2 (SEC2) is a classical superantigen (SAg), which can tremendously activate T lymphocytes at very low dosage, thus exerting its powerful antitumor activity. As an intravenous protein drug and a bacterial toxin, SEC2 has some limitations including poor patient compliance and toxic side effects. In this research, we devoted our attention to studying the antitumor activity and toxicity of SEC2 as a potential oral administration protein drug. We proved that His-tagged SEC2 (SEC2-His) could undergo facilitated transcytosis on human colon adenocarcinoma (Caco-2) cells and SEC2-His was detected in the blood of rats after oral administration. Furthermore, oral SEC2-His caused massive cytokine release and immune cell enrichment around tumor tissue, leading to inhibition of tumor growth in vivo. Meanwhile, although SEC2-His was dosed up to 32 mg/kg in mice, no significant toxicity was observed. These data showed that SEC2 can cross the intestinal epithelium in an immunologically integral form, maintaining antitumor activity but with reduced systemic toxicity. Therefore, these results may have implications for developing SEC2 as an oral administration protein drug. Full article
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Open AccessArticle Sequence Variability in Staphylococcal Enterotoxin Genes seb, sec, and sed
Toxins 2016, 8(6), 169; doi:10.3390/toxins8060169
Received: 3 May 2016 / Revised: 26 May 2016 / Accepted: 27 May 2016 / Published: 1 June 2016
Cited by 1 | PDF Full-text (1944 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Ingestion of staphylococcal enterotoxins preformed by Staphylococcus aureus in food leads to staphylococcal food poisoning, the most prevalent foodborne intoxication worldwide. There are five major staphylococcal enterotoxins: SEA, SEB, SEC, SED, and SEE. While variants of these toxins have been described and were
[...] Read more.
Ingestion of staphylococcal enterotoxins preformed by Staphylococcus aureus in food leads to staphylococcal food poisoning, the most prevalent foodborne intoxication worldwide. There are five major staphylococcal enterotoxins: SEA, SEB, SEC, SED, and SEE. While variants of these toxins have been described and were linked to specific hosts or levels or enterotoxin production, data on sequence variation is still limited. In this study, we aim to extend the knowledge on promoter and gene variants of the major enterotoxins SEB, SEC, and SED. To this end, we determined seb, sec, and sed promoter and gene sequences of a well-characterized set of enterotoxigenic Staphylococcus aureus strains originating from foodborne outbreaks, human infections, human nasal colonization, rabbits, and cattle. New nucleotide sequence variants were detected for all three enterotoxins and a novel amino acid sequence variant of SED was detected in a strain associated with human nasal colonization. While the seb promoter and gene sequences exhibited a high degree of variability, the sec and sed promoter and gene were more conserved. Interestingly, a truncated variant of sed was detected in all tested sed harboring rabbit strains. The generated data represents a further step towards improved understanding of strain-specific differences in enterotoxin expression and host-specific variation in enterotoxin sequences. Full article
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Open AccessReview Toxin-Antitoxin Systems of Staphylococcus aureus
Toxins 2016, 8(5), 140; doi:10.3390/toxins8050140
Received: 28 February 2016 / Revised: 21 April 2016 / Accepted: 25 April 2016 / Published: 5 May 2016
Cited by 6 | PDF Full-text (1439 KB) | HTML Full-text | XML Full-text
Abstract
Toxin-antitoxin (TA) systems are small genetic elements found in the majority of prokaryotes. They encode toxin proteins that interfere with vital cellular functions and are counteracted by antitoxins. Dependent on the chemical nature of the antitoxins (protein or RNA) and how they control
[...] Read more.
Toxin-antitoxin (TA) systems are small genetic elements found in the majority of prokaryotes. They encode toxin proteins that interfere with vital cellular functions and are counteracted by antitoxins. Dependent on the chemical nature of the antitoxins (protein or RNA) and how they control the activity of the toxin, TA systems are currently divided into six different types. Genes comprising the TA types I, II and III have been identified in Staphylococcus aureus. MazF, the toxin of the mazEF locus is a sequence-specific RNase that cleaves a number of transcripts, including those encoding pathogenicity factors. Two yefM-yoeB paralogs represent two independent, but auto-regulated TA systems that give rise to ribosome-dependent RNases. In addition, omega/epsilon/zeta constitutes a tripartite TA system that supposedly plays a role in the stabilization of resistance factors. The SprA1/SprA1AS and SprF1/SprG1 systems are post-transcriptionally regulated by RNA antitoxins and encode small membrane damaging proteins. TA systems controlled by interaction between toxin protein and antitoxin RNA have been identified in S. aureus in silico, but not yet experimentally proven. A closer inspection of possible links between TA systems and S. aureus pathophysiology will reveal, if these genetic loci may represent druggable targets. The modification of a staphylococcal TA toxin to a cyclopeptide antibiotic highlights the potential of TA systems as rather untapped sources of drug discovery. Full article
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Open AccessArticle Detection of Enterotoxigenic Potential and Determination of Clonal Profile in Staphylococcus aureus and Coagulase-Negative Staphylococci Isolated from Bovine Subclinical Mastitis in Different Brazilian States
Toxins 2016, 8(4), 104; doi:10.3390/toxins8040104
Received: 6 October 2015 / Revised: 15 January 2016 / Accepted: 20 January 2016 / Published: 15 April 2016
Cited by 2 | PDF Full-text (1529 KB) | HTML Full-text | XML Full-text
Abstract
Epidemiological studies have identified Staphylococcus aureus as the most common agent involved in food poisoning. However, current research highlights the importance of toxigenic coagulase-negative staphylococci (CoNS) isolated from food. The aim of this study was to characterize Staphylococcus spp. isolated from cows with
[...] Read more.
Epidemiological studies have identified Staphylococcus aureus as the most common agent involved in food poisoning. However, current research highlights the importance of toxigenic coagulase-negative staphylococci (CoNS) isolated from food. The aim of this study was to characterize Staphylococcus spp. isolated from cows with bovine subclinical mastitis regarding the presence of genes responsible for the production of staphylococcal enterotoxins and of the tst-1 gene encoding toxic shock syndrome toxin 1, and to determine the clonal profile of the isolates carrying any of the genes studied. A total of 181 strains isolated in different Brazilian states, including the South, Southeast, and Northeast regions, were analyzed. The sea gene was the most frequent, which was detected in 18.2% of the isolates, followed by seb in 7.7%, sec in 14.9%, sed in 0.5%, see in 8.2%, seg in 1.6%, seh in 25.4%, sei in 6.6%, and ser in 1.6%. The sej, ses, set, and tst-1 genes were not detected in any of the isolates. The typing of the isolates by pulsed-field gel electrophoresis revealed important S. aureus and S. epidermidis clusters in different areas and the presence of enterotoxin genes in lineages isolated from animals that belong to herds located geographically close to each other. Full article
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Open AccessArticle ADAM10 Cell Surface Expression but Not Activity Is Critical for Staphylococcus aureus α-Hemolysin-Mediated Activation of the NLRP3 Inflammasome in Human Monocytes
Toxins 2016, 8(4), 95; doi:10.3390/toxins8040095
Received: 4 January 2016 / Revised: 22 March 2016 / Accepted: 23 March 2016 / Published: 30 March 2016
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Abstract
The Staphylococcus aureus toxin, α-hemolysin, is an important and well-studied virulence factor in staphylococcal infection. It is a soluble monomeric protein that, once secreted by the bacterium, forms a heptameric pore in the membrane of a broad range of host cell types. Hemolysin
[...] Read more.
The Staphylococcus aureus toxin, α-hemolysin, is an important and well-studied virulence factor in staphylococcal infection. It is a soluble monomeric protein that, once secreted by the bacterium, forms a heptameric pore in the membrane of a broad range of host cell types. Hemolysin was recently discovered to bind and activate a disintegrin and metalloprotease 10 (ADAM10). In epithelial and endothelial cells, ADAM10 activation is required for the toxin’s activity against these cells. In host monocytic cells, α-hemolysin activates the nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 (NLRP3) inflammasome leading to production of pro-inflammatory cytokines and cell death. We now show that ADAM10 is critical for α-hemolysin-mediated activation of the NLRP3 inflammasome in human monocytes as siRNA knockdown or chemical blockade of ADAM10-α-hemolysin interaction leads to diminished inflammasome activation and cell death by reducing the available ADAM10 on the cell surface. Unlike epithelial cell and endothelial cell damage, which requires α-hemolysin induced ADAM10 activation, ADAM10 protease activity was not required for NLRP3 inflammasome activation. This work confirms the importance of ADAM10 in immune activation by α-hemolysin, but indicates that host cell signal induction by the toxin is different between host cell types. Full article
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Open AccessReview Targeting Staphylococcus aureus Toxins: A Potential form of Anti-Virulence Therapy
Toxins 2016, 8(3), 72; doi:10.3390/toxins8030072
Received: 18 February 2016 / Revised: 3 March 2016 / Accepted: 10 March 2016 / Published: 15 March 2016
Cited by 13 | PDF Full-text (2130 KB) | HTML Full-text | XML Full-text
Abstract
Staphylococcus aureus is an opportunistic pathogen and the leading cause of a wide range of severe clinical infections. The range of diseases reflects the diversity of virulence factors produced by this pathogen. To establish an infection in the host, S. aureus expresses an
[...] Read more.
Staphylococcus aureus is an opportunistic pathogen and the leading cause of a wide range of severe clinical infections. The range of diseases reflects the diversity of virulence factors produced by this pathogen. To establish an infection in the host, S. aureus expresses an inclusive set of virulence factors such as toxins, enzymes, adhesins, and other surface proteins that allow the pathogen to survive under extreme conditions and are essential for the bacteria’s ability to spread through tissues. Expression and secretion of this array of toxins and enzymes are tightly controlled by a number of regulatory systems. S. aureus is also notorious for its ability to resist the arsenal of currently available antibiotics and dissemination of various multidrug-resistant S. aureus clones limits therapeutic options for a S. aureus infection. Recently, the development of anti-virulence therapeutics that neutralize S. aureus toxins or block the pathways that regulate toxin production has shown potential in thwarting the bacteria’s acquisition of antibiotic resistance. In this review, we provide insights into the regulation of S. aureus toxin production and potential anti-virulence strategies that target S. aureus toxins. Full article
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Open AccessArticle Occurrence of Staphylococcus aureus on Farms with Small Scale Production of Raw Milk Cheeses in Poland
Toxins 2016, 8(3), 62; doi:10.3390/toxins8030062
Received: 3 December 2015 / Revised: 19 February 2016 / Accepted: 22 February 2016 / Published: 2 March 2016
Cited by 2 | PDF Full-text (723 KB) | HTML Full-text | XML Full-text
Abstract
This paper describes the results of a 3-year study on the prevalence, enterotoxinogenicity and resistance to antimicrobials of S. aureus isolated on dairy farms with small scale production of raw cow milk cheeses. The samples of raw milk, semi-finished products and the final
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This paper describes the results of a 3-year study on the prevalence, enterotoxinogenicity and resistance to antimicrobials of S. aureus isolated on dairy farms with small scale production of raw cow milk cheeses. The samples of raw milk, semi-finished products and the final products as well as swabs were collected between 2011 and 2013 from nine dairy farms in Poland. A total of 244 samples were examined, of which 122 (50.0%) were contaminated with S. aureus including 18 of 26 (69.2%) mature cheese samples with log10 CFU g−1 between <1- and 7.41. In swabs collected from the staff and production environment the highest contamination rate with coagulase positive staphylococci (CPS) was detected on hands of cheese makers (4.34 log10 CFU/swab). None of the cheese samples contaminated with CPS contained staphylococcal enterotoxins (SEs). However, 55 of 122 (45.1%) S. aureus isolates possessed SEs genes, mainly (26 of 55; 47.3%) a combination of the sed, sej and ser genes. Furthermore, the sep (15 of 55; 27.3%) as well as seg and sei (9 of 55; 16.4%) genes were also identified. The remaining S. aureus isolates possessed the sea gene (one isolate), the combination of sec, seg and sei (three isolates) as well as the sed, sej, sep and ser markers together (one CPS). Resistance to penicillin (62 of 122 isolates; 50.8%) was the most common among the tested isolates. Some CPS were also resistant to chloramphenicol (7; 5.7%) and tetracycline (5; 4.1%). The obtained results indicated that the analyzed cheeses were safe for consumers. To improve the microbiological quality of traditional cheese products more attention should be paid to animal welfare and hygiene practices during the process of cheese manufacturing in some dairy farms. Full article
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Open AccessArticle Prophage-Encoded Staphylococcal Enterotoxin A: Regulation of Production in Staphylococcus aureus Strains Representing Different Sea Regions
Toxins 2015, 7(12), 5359-5376; doi:10.3390/toxins7124889
Received: 11 October 2015 / Revised: 26 November 2015 / Accepted: 30 November 2015 / Published: 9 December 2015
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Abstract
The present study investigates the nature of the link between the staphylococcal enterotoxin A (SEA) gene and the lifecycle of Siphoviridae bacteriophages, including the origin of strain variation regarding SEA production after prophage induction. Five strains representing three different genetic lines of the
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The present study investigates the nature of the link between the staphylococcal enterotoxin A (SEA) gene and the lifecycle of Siphoviridae bacteriophages, including the origin of strain variation regarding SEA production after prophage induction. Five strains representing three different genetic lines of the sea region were studied under optimal and prophage-induced growth conditions and the Siphoviridae lifecycle was followed through the phage replicative form copies and transcripts of the lysogenic repressor, cro. The role of SOS response on prophage induction was addressed through recA transcription in a recA-disruption mutant. Prophage induction was found to increase the abundance of the phage replicative form, the sea gene copies and transcripts and enhance SEA production. Sequence analysis of the sea regions revealed that observed strain variances were related to strain capacity for prophage induction, rather than sequence differences in the sea region. The impact of SOS response activation on the phage lifecycle was demonstrated by the absence of phage replicative form copies in the recA-disruption mutant after prophage induction. From this study it emerges that all aspects of SEA-producing strain, the Siphoviridae phage and the food environment must be considered when evaluating SEA-related hazards. Full article
Open AccessArticle Superantigen-Producing Staphylococcus aureus Elicits Systemic Immune Activation in a Murine Wound Colonization Model
Toxins 2015, 7(12), 5308-5319; doi:10.3390/toxins7124886
Received: 12 October 2015 / Revised: 16 November 2015 / Accepted: 1 December 2015 / Published: 8 December 2015
Cited by 2 | PDF Full-text (2723 KB) | HTML Full-text | XML Full-text
Abstract
Staphylococcus aureus, the most common cause of wound infection, produces several exotoxins, including superantigens (SAgs). SAgs are the potent activators of the immune system. Given this unique property, we hypothesized that SAgs produced by S. aureus in wounds would have local, as
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Staphylococcus aureus, the most common cause of wound infection, produces several exotoxins, including superantigens (SAgs). SAgs are the potent activators of the immune system. Given this unique property, we hypothesized that SAgs produced by S. aureus in wounds would have local, as well as systemic immunologic effects. We tested our hypothesis using a novel staphylococcal skin wound infection model in transgenic mice expressing HLA-DR3. Skin wounds were left uninfected or colonized with S. aureus strains producing SAgs or an isogenic strain not producing any SAg. Animals with wounds challenged with SAg-producing S. aureus had increased morbidity and lower serum IL-17 levels compared to those challenged with the SAg non-producing S. aureus (p = 0.027 and p = 0.032, respectively). At Day 8 following microbial challenge, compared to mice with uninfected wounds, the proportion of Vβ8+CD4+ T cells was increased, while the proportion of Vβ8+CD8+ T cells was decreased only in the spleens of mice challenged with SAg-producing S. aureus (p < 0.001). No such changes were measured in mice challenged with SAg non-producing S. aureus. Lungs, livers and kidneys from mice challenged with SAg-producing, but not SAg non-producing, S. aureus showed inflammatory changes. Overall, SAg-mediated systemic immune activation in wounds harboring S. aureus may have clinical implications. Full article
Open AccessArticle EDIN-B Promotes the Translocation of Staphylococcus aureus to the Bloodstream in the Course of Pneumonia
Toxins 2015, 7(10), 4131-4142; doi:10.3390/toxins7104131
Received: 18 August 2015 / Revised: 25 September 2015 / Accepted: 30 September 2015 / Published: 15 October 2015
Cited by 1 | PDF Full-text (972 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
It is crucial to define risk factors that contribute to host invasion by Staphylococcus aureus. Here, we demonstrate that the chromosomally encoded EDIN-B isoform from S. aureus contributes to the onset of bacteremia during the course of pneumonia. Deletion of edinB in
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It is crucial to define risk factors that contribute to host invasion by Staphylococcus aureus. Here, we demonstrate that the chromosomally encoded EDIN-B isoform from S. aureus contributes to the onset of bacteremia during the course of pneumonia. Deletion of edinB in a European lineage community-acquired methicillin resistant S. aureus (CA-MRSA) strain (ST80-MRSA-IV) dramatically decreased the frequency and magnitude of bacteremia in mice suffering from pneumonia. This deletion had no effect on the bacterial burden in both blood circulation and lung tissues. Re-expression of wild-type EDIN-B, unlike the catalytically inactive mutant EDIN-R185E, restored the invasive characteristics of ST80-MRSA-IV. Full article

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