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Salmonella Typhi is a human host-restricted pathogen that is responsible for typhoid fever in approximately 10.9 million people annually 1 . The typhoid toxin is postulated to have a central role in disease pathogenesis, the establishment of chronic infection and human host restriction 2 – 6 . However, its precise role in typhoid disease in humans is not fully defined. We studied the role of typhoid toxin in acute infection using a randomized, double-blind S. Typhi human challenge model 7 . Forty healthy volunteers were randomized (1:1) to oral challenge with 10 4 colony-forming units of wild-type or an isogenic typhoid toxin deletion mutant (TN) of S. Typhi. We observed no significant difference in the rate of typhoid infection (fever ≥38 °C for ≥12 h and/or S . Typhi bacteremia) between participants challenged with wild-type or TN S . Typhi (15 out of 21 (71%) versus 15 out of 19 (79%); P  = 0.58). The duration of bacteremia was significantly longer in participants challenged with the TN strain compared with wild-type (47.6 hours (28.9–97.0) versus 30.3(3.6–49.4); P ≤ 0.001). The clinical syndrome was otherwise indistinguishable between wild-type and TN groups. These data suggest that the typhoid toxin is not required for infection and the development of early typhoid fever symptoms within the context of a human challenge model. Further clinical data are required to assess the role of typhoid toxin in severe disease or the establishment of bacterial carriage. Typhoid toxin is not essential for the pathogenesis of typhoid fever in healthy humans challenged with Salmonella Typhi.

The largest burden of typhoid fever falls on the developing world. Because there is no simple diagnostic test for salmonella infections, the importance of typhoid is often underestimated. Complications include gastrointestinal bleeding, intestinal perforation, and encephalopathy. For decades, cheap, effective oral antibiotics have been available, but the situation is changing with the emergence of resistant organisms. With the new conjugate Vi vaccine, mass-vaccination programs may be an attractive option. Typhoid fever is a systemic infection with the bacterium Salmonella enterica serotype typhi. This highly adapted, human-specific pathogen has evolved remarkable mechanisms for persistence in its host that help to ensure its survival and transmission. Typhoid fever was an important cause of illness and death in the overcrowded and unsanitary urban conditions of the United States and Europe in the 19th century. 1 The provision of clean water and good sewage systems led to a dramatic decrease in the incidence of typhoid in these regions. Today most of the burden of the disease occurs in the developing world, where sanitary conditions . . .

BACKGROUND: Current recommendations are that HIV-infected persons should not be given live vaccines. We set out to assess potential toxicity of three live, attenuated oral vaccines (against rotavirus, typhoid and ETEC) in a phase 1 study. METHODS: Two commercially available oral vaccines against rotavirus (Rotarix) and typhoid (Vivotif) and one candidate vaccine against Enterotoxigenic Escherichia coli (ACAM2017) were given to HIV seropositive (n=42) and HIV seronegative (n=59) adults. Gastrointestinal symptoms were sought actively by weekly interview up to 1 month of vaccination. In rotavirus vaccine recipients, intestinal biopsies were collected by endoscopy and evaluated for expression of IL-8 and pro-inflammatory cytokines. RESULTS: No difference was observed between symptoms in HIV infected and HIV uninfected vaccinees, except for diarrhoea reported more than 7 days after the last dose of vaccine. If only diarrhoea episodes within 7 days of vaccination are included, diarrhoea was not more frequent in HIV seropositive than in HIV seronegative vaccinees (OR 6.7, 95% CI 1.2–67; P=0.09). However, if later episodes of diarrhoea are included, a significant increase in diarrhoea was demonstrated (OR 5.3, 95% CI 0.98–53; P=0.04). All episodes were mild and transient. IL-8 was slowly up-regulated over the week following vaccination (P=0.02), but IL-β, IFNγ or TNFα were not. CONCLUSIONS: No evidence was found of adverse events following administration of these three vaccines, except for late episodes of diarrhoea which may not be attributable to vaccination. Our data do not support the need for a prohibition on oral administration of live, attenuated vaccines to all HIV infected adults, though further work on severely immunocompromised adults and children are required.

Enteric fever is caused by Salmonella enterica serovar Typhi (S. Typhi) and Salmonella enterica serovar Paratyphi (S. Paratyphi) A, B, and C. Globally, an estimated 11 to 21 million cases of typhoid and paratyphoid fever occur annually, with approximately 130,000–160,000 deaths, most of which are reported in South/Southeast Asia and sub-Saharan Africa. The antibiotic susceptibility of S. Typhi strains varies between countries within broad limits, from 3% to 97% for ampicillin, 9% to 95% for ciprofloxacin, 4% to 94% for chloramphenicol (India vs. Pakistan), and 0% to 99% for ceftriaxone (India vs. Iraq). With S. Typhi increasingly exhibiting resistance to antibiotics, vaccination becomes an essential preventive measure. Currently, three vaccines are licensed for typhoid fever: the typhoid conjugate vaccine (TCV), live-attenuated oral vaccine Ty21a (Ty21a), and Vi capsular polysaccharide vaccine (Vi-CPS). While no specific vaccine exists for paratyphoid fever, the genetic and antigenic similarities between S. Paratyphi and S. Typhi offer potential for the development of such a vaccine. Early studies show promising results, demonstrating both safety and immunogenicity in preclinical trials. Whole genome sequencing (WGS) provides a powerful tool for assigning genotypes, identifying plasmids, comparing genetic elements, and investigating molecular factors that contribute to antibiotic resistance and virulence.

There is paucity of data regarding the geographical distribution, incidence, and phylogenetics of multi-drug resistant (MDR) Salmonella Typhi in sub-Saharan Africa. Here we present a phylogenetic reconstruction of whole genome sequenced 249 contemporaneous S . Typhi isolated between 2008-2015 in 11 sub-Saharan African countries, in context of the 2,057 global S . Typhi genomic framework. Despite the broad genetic diversity, the majority of organisms (225/249; 90%) belong to only three genotypes, 4.3.1 (H58) (99/249; 40%), 3.1.1 (97/249; 39%), and 2.3.2 (29/249; 12%). Genotypes 4.3.1 and 3.1.1 are confined within East and West Africa, respectively. MDR phenotype is found in over 50% of organisms restricted within these dominant genotypes. High incidences of MDR S . Typhi are calculated in locations with a high burden of typhoid, specifically in children aged <15 years. Antimicrobial stewardship, MDR surveillance, and the introduction of typhoid conjugate vaccines will be critical for the control of MDR typhoid in Africa. Typhoid fever is caused by the bacterium Salmonella Typhi. Here, Park et al. analyse the genomes of 249 S . Typhi isolates from 11 sub-Saharan African countries, identifying genes and plasmids associated with antibiotic resistance and showing that multi-drug resistance is highly pervasive in sub-Saharan Africa.

Salmonella Typhi ( S . Typhi) is a Gram-negative bacterium that exclusively infects humans and causes typhoid fever– a major global public health concern responsible for approximately 9 million infections and 110,000 deaths annually. Macrophages, a key component of the innate immune system, play essential roles in pathogen clearance, antigen presentation, immune regulation, and tissue repair. As one of the primary targets of S . Typhi infection, macrophages significantly influence disease onset and progression. S . Typhi expresses a range of virulence factors, including the virulence-associated (Vi) capsule, outer membrane proteins (OMPs), flagella, fimbriae, type III secretion systems (T3SSs) and other genes encoded on Salmonella pathogenicity islands (SPIs), as well as toxins, regulatory factors, and virulence plasmids. These virulence factors facilitate S . Typhi’s intracellular survival within macrophages by mediating processes such as adhesion, invasion, nutrient acquisition and immune evasion, ultimately enabling systemic infection. This review explores the role and molecular mechanisms of S . Typhi virulence factors in counteracting macrophage antimicrobial functions, providing insights for future research on typhoid pathogenesis and the development of potential therapeutic interventions.

Salmonella enterica subsp. enterica contains more than 2,600 serovars of which four are of major medical relevance for humans. While the typhoidal serovars (Typhi and Paratyphi A) are human-restricted and cause enteric fever, non-typhoidal Salmonella serovars (Typhimurium and Enteritidis) have a broad host range and predominantly cause gastroenteritis. We compared the core proteomes of Salmonella Typhi, Paratyphi A, Typhimurium and Enteritidis using contemporary proteomics. For each serovar, five clinical isolates (covering different geographical origins) and one reference strain were grown in vitro to the exponential phase. Levels of orthologous proteins quantified in all four serovars and within the typhoidal and non-typhoidal groups were compared and subjected to gene ontology term enrichment and inferred regulatory interactions. Differential expression of the core proteomes of the typhoidal serovars appears mainly related to cell surface components and, for the non-typhoidal serovars, to pathogenicity. Our comparative proteome analysis indicated differences in the expression of surface proteins between Salmonella Typhi and Paratyphi A, and in pathogenesis-related proteins between Salmonella Typhimurium and Enteritidis. Our findings may guide future development of novel diagnostics and vaccines, as well as understanding of disease progression.

Salmonella enterica represents a major human and animal pathogen. Many S. enterica genomes have been completed and many more genome sequencing projects are underway, constituting an excellent resource for comparative genome analysis studies leading to a better understanding of bacterial evolution and pathogenesis. Salmonella enterica serovar Typhimurium and Typhi are the best-characterized serovars, with the first being involved in localized gastroenteritis in many hosts and the latter causing a systemic human-specific disease. Here, we summarize the major genetic differences between the two different serovars. We detail the divergent repertoires of the virulence factors responsible for the pathogenesis of the organisms and that ultimately result in the distinct clinical outcomes of infection. This comparative genomic overview highlights hypotheses for future investigations on S. enterica pathogenesis and the basis of host specificity.

Salmonella enterica serovar Typhi ( S . Typhi) is a leading cause of typhoid fever, significantly impacting morbidity and mortality in Ghana. However, genome-resolved data on circulating typhoidal strains remains scarce. We conducted this study to explore the genetic diversity, virulence, and antimicrobial resistance (AMR) profiles of S . enterica strains isolated from clinically diagnosed typhoid patients to inform targeted management and surveillance strategies. Twenty-eight S . enterica isolates recovered from stool and blood cultures were confirmed by PCR targeting 211 bp amplicon of the bcfD gene. Whole-genome sequencing was performed on all isolates followed by multi-locus sequence typing (MLST), SPIFinder, ResFinder, and phylogenetic analyses to characterize sequence types (STs), virulence markers, including antibiotic resistance genes and to define clonal relatedness. The GenoTyphi program was used to assign isolates within known S . Typhi lineages. For regional comparison, publicly available S . enterica genomes and their corresponding metadata were retrieved from the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) and Pathogenwatch and included in the phylogenetic analysis. MLST revealed significant genetic diversity, with S . Typhi ST02 and S . Typhimurium ST19 and ST313 being notable. ST02 isolates, predominantly linked to typhoidal strains, formed distinct clusters with isolates from neighboring West African countries, indicating regional transmission dynamics. ST313, associated with invasive infections, was isolated from stool samples. The study identified a high prevalence of virulence genes such as invA , invE , sopB , sopD , cdtB , pltA , and pltB among STs that are not implicated in typhoidal salmonellosis. Plasmid analysis showed limited diversity, with plasmid replicons detected in only a subset of isolates (n = 12/28, 42.9%). Plasmid carriage was universal in S. Typhimurium (4/4, 100%), dominated by IncFIB(S) and IncFII(S), with IncQ1 also detected in two isolates. In contrast, plasmids were rare in S. Typhi (1/6, 16.7%), where only a single isolate harbored IncFIB(S) and IncFII(S). Other non-typhoidal serovars (n = 18) showed moderate carriage (7/18, 38.9%) and greater plasmid diversity. In addition to IncF-type replicons, these isolates harbored Col(pHAD28), IncN, and IncFIB(K). Antibiotic resistance genes were detected at low frequencies, including bla TEM variants (beta-lactam resistance, n = 3), qnr (quinolone resistance, n = 3), sul1 / sul2 (sulfonamide resistance, n = 3), aadA1 , aph(6)-Id , aac(3)-IIa (aminoglycoside-modifying enzymes, n = 3) , tet(A ) (tetracycline resistance, n = 2), dfrA1 (trimethoprim resistance, n = 1), and catA1 (chloramphenicol resistance, n = 1), highlighting limited antimicrobial resistance potential in the populations sampled. The serovars identified were S . Typhi (n = 6), S . Infantis (n = 4), S . Virchow (n = 4), S . Chester (n = 2), S . Jukestown (n = 1), S . Durham (n = 4), S . Typhimurium (n = 4), S . Wein (n = 1), S . Bangui (n = 1) and S . Saintpaul (n = 1). Phylogenetic analysis positioned the isolates recovered from the current study within clades of other regional isolates with global clinical relevance. The S . Typhi isolates belonged to lineage 3.2.1, not previously reported in Ghana, and not typically associated with multidrug resistance. This study provides an important insight into the genetic characteristics of S . enterica strains associated with typhoid fever among Ghanaian patients. Several non-typhoidal Salmonella (NTS) strains were found to harbor virulence determinants, including toxin-associated genes implicated in typhoid pathogenesis, highlighting their potential clinical relevance.

Measuring the burden of typhoid fever and developing effective strategies to reduce it require a surveillance infrastructure that is currently lacking in many endemic countries. Recent efforts and partnerships between local and international researchers have helped to provide new data on the incidence and control of typhoid in parts of Asia and Africa. Here, we highlight examples from India, Nepal, Vietnam, Fiji, Sierra Leone, and Malawi that summarize past and present experiences with the diagnosis, treatment, and prevention of typhoid fever in different locations with endemic disease. While there is no validated road map for the elimination of typhoid, the lessons learned in studying the epidemiology and control of typhoid in these settings can provide insights to guide future disease control efforts.