Search Results (16)

Background: Typhoid and paratyphoid fevers represent a global health burden, especially in Southern Asia, exacerbated by the increase in antimicrobial resistance. While vaccines against Salmonella Typhi have been successfully introduced, a vaccine against S. Paratyphi A is not available, yet. Efforts to develop an effective vaccine targeting both Salmonella serovars are currently ongoing. GVGH is developing a bivalent vaccine constituted by the Vi-CRM₁₉₇ typhoid conjugate vaccine (TCV), and the Salmonella Paratyphi A O-antigen (O:2), also conjugated to the CRM₁₉₇ carrier protein (O:2-CRM₁₉₇). In this work we have characterized a panel of S. Paratyphi A clinical isolates from endemic regions, differing in terms of their O:2 structural features. Methods: Rabbits were immunized with the S. Paratyphi A component of the vaccine candidate and the resulting sera were tested for their ability to bind and kill the isolates using flow cytometry and luminescence-based serum bactericidal assay (L-SBA). Results: The O:2-CRM₁₉₇ glycoconjugate induced a functional immune response in rabbits, effectively binding and killing a diverse panel of clinical isolates. The sera demonstrated bactericidal activity independent of the O:2 structural variations, including differences in O-acetylation and glucosylation levels. Additionally, the study found that the O:2-CRM₁₉₇ conjugate’s adsorption to Alhydrogel did not significantly impact its immunogenicity or bactericidal efficacy. Conclusions: The O:2-CRM₁₉₇ component of the bivalent vaccine candidate shows promise in providing broad protection against S. Paratyphi A isolates, regardless of their O-antigen structural variations. The ongoing clinical studies on human sera are expected to confirm these results. Full article

Background/Objectives: Typhoid and paratyphoid fever together are responsible for millions of cases and thousands of deaths per year, most of which occur in children in South and Southeast Asia. While typhoid conjugate vaccines (TCVs) are licensed, no vaccines are currently available against S. Paratyphi A. Here we describe the design of a S. Paratyphi A conjugate. Methods: The serovar-specific O-antigen (O:2) was linked to the CRM₁₉₇ carrier protein (O:2–CRM₁₉₇) and a panel of conjugates differing for structural characteristics were compared in mice and rabbits. Results: We identified the O-antigen molecular size, polysaccharide to protein ratio, conjugate cross-linking, and O:2 O-acetylation level as critical quality attributes and identified optimal design for a more immunogenic vaccine. Conclusions: This work guides the development of the O:2–CRM₁₉₇ conjugate to be combined with TCV in a bivalent formulation against enteric fever. Full article

Gallbladder carcinoma represents the most aggressive biliary tract cancer and the sixth most common gastrointestinal malignancy. The diagnosis is a challenging clinical task due to its clinical presentation, which is often non-specific, mimicking a heterogeneous group of diseases, as well as benign processes such as complicated cholecystitis, xanthogranulomatous cholecystitis, adenomyomatosis, porcelain gallbladder or metastasis to the gallbladder (most frequently derived from melanoma, renal cell carcinoma). Risk factors include gallstones, carcinogen exposure, porcelain gallbladder, typhoid carrier state, gallbladder polyps and abnormal pancreaticobiliary ductal junction. Typical imaging features on CT or MRI reveal three major patterns: asymmetric focal or diffuse wall-thickening of the gallbladder, a solid mass that replaces the gallbladder and invades the adjacent organs or as an intraluminal enhancement mass arising predominantly from the gallbladder fundus. The tumor can spread to the liver, the adjacent internal organs and lymph nodes. Depending on the disease stage, surgical resection is the curative treatment option in early stages and adjuvant combination chemotherapy at advanced stages. The purpose of this scientific paper is to fully illustrate and evaluate, through multimodality imaging findings (CT and MRI), different presentations and imaging scenarios of gallbladder cancer in six patients and thoroughly analyze the risk factors, patterns of spread and differential diagnosis regarding each particular case. Full article

Despite major progress in the last several decades in reducing the public and animal health burden of infectious disease a number of issues remain to be resolved and which have thus far been regarded as intractable. These include (i) the persistent carrier state in individuals convalescent from typhoid and typhoid-like infections, (ii) the increasing prevalence of multi-antibiotic resistance in enteric pathogens, much of which is mediated by self-transmissible plasmids, and (iii) parasite infections which are difficult to control by vaccination and where resistance to chemotherapeutics is also increasing. The author describes very recent work carried out by his group to look at resolving these problems in new and imaginative ways. Full article

Typhoid fever is a significant public health concern in many parts of the world, particularly in developing countries with poor sanitation and hygiene conditions. In July 2016, an outbreak of typhoid fever occurred in Ghannouche, located in the south of Tunisia. This paper reports the results of a field investigation undertaken to identify possible transmission pathways and risk factors in order to propose control and preventive measures. A retrospective cohort study including a passive and active case finding, as well as an environmental and bacteriological investigation was conducted from July to September 2016. A case was defined as a person residing or having stayed in Ghannouche and having presented from the beginning of June clinical signs suggestive of typhoid fever, with, for a confirmed case, laboratory isolation of S.Tyhi, and for a probable case, an epidemiological link with a confirmed case. Attack rates were determined, and risk ratios were estimated with respect to exposures. Unadjusted and adjusted odds ratios were estimated using binary logistic regression. Among the 628 subjects investigated, 102 cases of typhoid fever were identified (74 confirmed and 28 probable) with an overall attack rate of 16.24%. Over 56% of cases were male and those under 10 years old were most affected (38.2%% of cases) with a median age of 12 years (interquartile range 5 to 25 years). The main clinical signs were fever (95%) and diarrhea (57%). Young age (adjusted OR = 0.95 and 95% CI = 0.93–0.97), low level of education (adjusted OR = 4.76 and 95% CI = 1.34–16.81), and the habitat type Arab or rudimentary house (adjusted OR = 4.93 and 95% CI = 2.61–8.27) were the socio-demographic factors independently associated with typhoid fever. Typhoid fever was found to be associated with drinking softened water (adjusted OR = 2.64 and 95% CI = 1.16–4.82), eating raw fruit and vegetables from family gardens (adjusted OR = 6.13 and 95% CI = 3.66–11.06), and using uncontrolled waste disposal (adjusted OR = 3.52 and 95% CI = 2.03–6.94). A total of 110 drinking water samples were analyzed; out of the 38 samples of softened water, 12 were non-compliant and 5 were positive for Salmonella. The screening activity identified two asymptomatic carriers, one of whom was a softened water seller. We concluded that drinking softened water from informal or unauthorized sale units, consuming fruit and vegetables from family gardens, uncontrolled dumping of household waste, and poor socio-economic conditions increase the risk of typhoid fever in this region. Many recommendations were implemented to stop this outbreak and to prevent further episodes. Full article

Typhoid fever remains a significant public health concern due to cases of mis-/overdiagnosis. Asymptomatic carriers play a role in the transmission and persistence of typhoid fever, especially among children, where limited data exist in Nigeria and other endemic countries. We aim to elucidate the burden of typhoid fever among healthy school-aged children using the best surveillance tool(s). In a semi-urban/urban state (Osun), 120 healthy school-aged children under 15 years were enrolled. Whole blood and fecal samples were obtained from consenting children. ELISA targeting the antigen lipopolysaccharide (LPS) and anti-LPS antibodies of Salmonella Typhi, culture, polymerase chain reaction (PCR), and next-generation sequencing (NGS) were used to analyze the samples. At least one of the immunological markers was detected in 65.8% of children, with 40.8%, 37.5%, and 39% of children testing positive for IgM, IgG, and antigen, respectively. Culture, PCR, and NGS assays did not detect the presence of Salmonella Typhi in the isolates. This study demonstrates a high seroprevalence of Salmonella Typhi in these healthy children but no carriage, indicating the inability to sustain transmission. We also demonstrate that using a single technique is insufficient for typhoid fever surveillance in healthy children living in endemic areas. Full article

Bacterial infections are common in the etiology of human diseases owing to the ubiquity of bacteria. Such infections promote the development of periodontal disease, bacterial pneumonia, typhoid, acute gastroenteritis, and diarrhea in susceptible hosts. These diseases may be resolved using antibiotics/antimicrobial therapy in some hosts. However, other hosts may be unable to eliminate the bacteria, allowing them to persist for long durations and significantly increasing the carrier's risk of developing cancer over time. Indeed, infectious pathogens are modifiable cancer risk factors, and through this comprehensive review, we highlight the complex relationship between bacterial infections and the development of several cancer types. For this review, searches were performed on the PubMed, Embase, and Web of Science databases encompassing the entirety of 2022. Based on our investigation, we found several critical associations, of which some are causative: Porphyromonas gingivalis and Fusobacterium nucleatum are associated with periodontal disease, Salmonella spp., Clostridium perfringens, Escherichia coli, Campylobacter spp., and Shigella are associated with gastroenteritis. Helicobacter pylori infection is implicated in the etiology of gastric cancer, and persistent Chlamydia infections present a risk factor for the development of cervical carcinoma, especially in patients with the human papillomavirus (HPV) coinfection. Salmonella typhi infections are linked with gallbladder cancer, and Chlamydia pneumoniae infection is implicated in lung cancer, etc. This knowledge helps identify the adaptation strategies used by bacteria to evade antibiotic/antimicrobial therapy. The article also sheds light on the role of antibiotics in cancer treatment, the consequences of their use, and strategies for limiting antibiotic resistance. Finally, the dual role of bacteria in cancer development as well as in cancer therapy is briefly discussed, as this is an area that may help to facilitate the development of novel microbe-based therapeutics as a means of securing improved outcomes. Full article

Typhoid fever is caused by Salmonella enterica serovar Typhi (S. Typhi). Around 3–5% of individuals infected become chronic carriers, with the gallbladder (GB) as the predominant site of persistence. Gallstones (GS) aid in the development and maintenance of GB carriage, serving as a substrate to which Salmonellae attach and form a biofilm. This biofilm matrix protects bacteria from the host immune system and environmental stress. This shielded environment is an ideal place for the development of persister cells, a transient phenotype of a subset of cells within a population that allows survival after antibiotic treatment. Persisters can also arise in response to harsh environments such as the GB. Here we investigate if GB conditions affect the number of persisters in a Salmonella population. To simulate the chronic GB environment, we cultured biofilms in cholesterol-coated 96-well plates in the presence of ox or human bile. We then treated planktonic or biofilm Salmonella cultures with high concentrations of different antibiotics. This study suggests that biofilms provide a niche for persister cells, but GB conditions either play no role or have a negative influence on persister formation, especially after kanamycin treatment. The antibiotic target was important, as antimicrobials directed against DNA replication or the cell wall had no effect on persister cell formation. Interestingly, repeated treatment with ciprofloxacin increased the percentage of S. Typhimurium persisters in a biofilm, but this increase was abolished by GB conditions. On the other hand, repeated ciprofloxacin treatment of S. Typhi biofilms in GB conditions slightly increased the fraction of persisters. Thus, while the harsh conditions in the GB would be thought to give rise to increased persisters, therefore contributing to the development of chronic carriage, these data suggest persister cell formation is dampened in this environment. Full article

The enteric system residing notorious Salmonella typhimurium (S. typhi) is an intracellular, food-borne, and zoonotic pathogen causing typhoid fever. Typhoid fever is one of the leading causes of mortality and morbidity in developing and underdeveloped countries. It also increased the prevalence of multidrug resistance globally. Currently, available anti-bacterial modalities are unable to penetrate into the intracellular compartments effectively for eradicating S. typhi infection. Therefore, in this study, we developed nanostructured lipid-based carriers in the form of a self-nanoemulsifying drug delivery system (SNEDDS) for targeted delivery of ciprofloxacin (CIP) into the S. typhi intracellular reservoirs. Capryol 90, Tween 80, and Span 20 were finalized as suitable oil, surfactant, and co-surfactant, respectively, according to the pseudoternary phase diagram emulsifying region. Targeting capability and mucopenetration of the SNEDDS was attributed to the inclusion of amidated pluronic (NH₂-F₁₂₇). Developed NH₂-F₁₂₇ SNEDDS were characterized via physicochemical, in vitro, ex vivo, and in vivo evaluation parameters. The size of the SNEDDS was found to be 250 nm, having positively charged zeta potential. In vitro dissolution of SNEDDS showed 80% sustained release of CIP in 72 h with maximum entrapment efficiency up to 90% as well as good hemocompatibility by showing less than 0.2% hemolysis and 90% biocompatibility. The survival rate of S. typhi in macrophages (RAW 264.7) was minimal, i.e., only 2% in the case of NH₂-F₁₂₇ SNEDDS. Macrophage uptake assay via nanostructures confirmed the maximum cellular uptake as evidenced by the highest fluorescence. Biofilm dispersion assay showed rapid eradication of developed resistant biofilms on the gall bladder. In vivo pharmacokinetics showed improved bioavailability by showing an increased area under the curve (AUC) value. Taken together, NH₂-F₁₂₇-SNEDDS can be utilized as an alternative and efficient delivery system for the sustained release of therapeutic amounts of CIP for the treatment of S. typhi. Full article

Salmonella enterica serovar Typhi (S. typhi) is an intracellular pathogen belonging to the Enterobacteriaceae family, where biofilm (aggregation and colonization of cells) formation is one of their advantageous traits. Salmonella typhi is the causative agent of typhoid fever in the human body and is exceptionally host specific. It is transmitted through the fecal–oral route by consuming contaminated food or water. This subspecies is quite intelligent to evade the innate detection and immune response of the host body, leading to systemic dissemination. Consequently, during the period of illness, the gallbladder becomes a harbor and may develop antibiotic resistance. Afterwards, they start contributing to the continuous damage of epithelium cells and make the host asymptomatic and potential carriers of this pathogen for an extended period. Statistically, almost 5% of infected people with Salmonella typhi become chronic carriers and are ready to contribute to future transmission by biofilm formation. Biofilm development is already recognized to link with pathogenicity and plays a crucial role in persistency within the human body. This review seeks to discuss some of the crucial factors related to biofilm development and its mechanism of interaction causing pathogenicity. Understanding the connections between these things will open up a new avenue for finding therapeutic approaches to combat pathogenicity. Full article

One characteristic of the few Salmonella enterica serovars that produce typhoid-like infections is that disease-free persistent infection can occur for months or years in a small number of individuals post-convalescence. The bacteria continue to be shed intermittently which is a key component of the epidemiology of these infections. Persistent chronic infection occurs despite high levels of circulating specific IgG. We have reviewed the information on the basis for persistence in S. Typhi, S. Dublin, S. Gallinarum, S. Pullorum, S. Abortusovis and also S. Typhimurium in mice as a model of persistence. Persistence appears to occur in macrophages in the spleen and liver with shedding either from the gall bladder and gut or the reproductive tract. The involvement of host genetic background in defining persistence is clear from studies with the mouse but less so with human and poultry infections. There is increasing evidence that the organisms (i) modulate the host response away from the typical Th1-type response normally associated with immune clearance of an acute infection to Th2-type or an anti-inflammatory response, and that (ii) the bacteria modulate transformation of macrophage from M1 to M2 type. The bacterial factors involved in this are not yet fully understood. There are early indications that it might be possible to remodulate the response back towards a Th1 response by using cytokine therapy. Full article

A multiplex rapid detection system, based on a PCR-lateral flow biosensor (mPCR-LFB) was developed to identify Salmonella Typhi and Salmonella Paratyphi A from suspected carriers. The lower detection limit for S. Typhi and S. Paratyphi A was 0.16 and 0.08 ng DNA equivalent to 10 and 10² CFU/mL, respectively. Lateral flow biosensor was used for visual detection of mPCR amplicons (stgA, SPAint, ompC, internal amplification control) by labeling forward primers with fluorescein-isothiocyanate (FITC), Texas Red, dinitrophenol (DNP) and digoxigenin (DIG) and reverse primers with biotin. Binding of streptavidin-colloidal gold conjugate with the amplicons resulted in formation of a red color dots on the strip after 15–20 min of sample exposure. The nucleic acid lateral flow analysis of the mPCR-LFB was better in sensitivity and more rapid than the conventional agarose gel electrophoresis. Moreover, the mPCR-LFB showed 100% sensitivity and specificity when evaluated with stools spiked with 100 isolates of Salmonella genus and other bacteria. A prospective cohort study on stool samples of 1176 food handlers in outbreak areas (suspected carriers) resulted in 23 (2%) positive for S. Typhi. The developed assay has potential to be used for rapid detection of typhoid carriers in surveillance program. Full article

Typhoid fever remains a significant health problem in sub-Saharan Africa, with incidence rates of >100 cases per 100,000 person-years of observation. Despite the prequalification of safe and effective typhoid conjugate vaccines (TCV), some uncertainties remain around future demand. Real-life effectiveness data, which inform public health programs on the impact of TCVs in reducing typhoid-related mortality and morbidity, from an African setting may help encourage the introduction of TCVs in high-burden settings. Here, we describe a cluster-randomized trial to investigate population-level protection of TYPBAR-TCV^®, a Vi-polysaccharide conjugated to a tetanus-toxoid protein carrier (Vi-TT) against blood-culture-confirmed typhoid fever, and the synthesis of health economic evidence to inform policy decisions. A total of 80 geographically distinct clusters are delineated within the Agogo district of the Asante Akim region in Ghana. Clusters are randomized to the intervention arm receiving Vi-TT or a control arm receiving the meningococcal A conjugate vaccine. The primary study endpoint is the total protection of Vi-TT against blood-culture-confirmed typhoid fever. Total, direct, and indirect protection are measured as secondary outcomes. Blood-culture-based enhanced surveillance enables the estimation of incidence rates in the intervention and control clusters. Evaluation of the real-world impact of TCVs and evidence synthesis improve the uptake of prequalified/licensed safe and effective typhoid vaccines in public health programs of high burden settings. This trial is registered at the Pan African Clinical Trial Registry, accessible at Pan African Clinical Trials Registry (ID: PACTR202011804563392). Full article

Salmonella enterica serovar Typhi (S. Typhi) and S. Paratyphi, namely typhoidal Salmonellae, are the cause of (para) typhoid fever, which is a devastating systemic infectious disease in humans. In addition, the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) S. Typhi in many low and middle-income countries poses a significant risk to human health. While currently available typhoid vaccines and therapeutics are efficacious, they have some limitations. One important limitation is the lack of controlling individuals who chronically carry S. Typhi. However, due to the strict host specificity of S. Typhi to humans, S. Typhi research is hampered. As a result, our understanding of S. Typhi pathogenesis is incomplete, thereby delaying the development and improvement of prevention and treatment strategies. Nonetheless, to better combat and contain S. Typhi, it is vital to develop a vaccine and therapy for controlling both acutely and chronically infected individuals. This review discusses how scientists are trying to combat typhoid fever, why it is so challenging to do so, which approaches show promise, and what we know about the pathogenesis of S. Typhi chronic infection. Full article

Salmonella enterica subspecies enterica serovar Typhi is the aetiological agent of typhoid or enteric fever. In a subset of individuals, S. Typhi colonizes the gallbladder causing an asymptomatic chronic infection. Nonetheless, these asymptomatic carriers provide a reservoir for further spreading of the disease. Epidemiological studies performed in regions where S. Typhi is endemic, revealed that the majority of chronically infected carriers also harbour gallstones, which in turn, have been indicated as a primary predisposing factor for the onset of gallbladder cancer (GC). It is now well recognised, that S. Typhi produces a typhoid toxin with a carcinogenic potential, that induces DNA damage and cell cycle alterations in intoxicated cells. In addition, biofilm production by S. Typhi may represent a key factor for the promotion of a persistent infection in the gallbladder, thus sustaining a chronic local inflammatory response and exposing the epithelium to repeated damage caused by carcinogenic toxins. This review aims to highlight the putative connection between the chronic colonization by highly pathogenic strains of S. Typhi capable of combining biofilm and toxin production and the onset of GC. Considering the high risk of GC associated with the asymptomatic carrier status, the rapid identification and profiling of biofilm production by S. Typhi strains would be key for effective therapeutic management and cancer prevention. Full article