RARE DISEASE
Typhoid
Typhoid
Typhoid
Synonyms: Typhoid fever, Typhoidal salmonellosis
Synonyms: Typhoid fever, Typhoidal salmonellosis
Synonyms: Typhoid fever, Typhoidal salmonellosis
Drug discovery
2,653
papers
On emerging therapies
Overview
Typhoid fever, caused by Salmonella enterica serotype Typhi, is a systemic illness transmitted via contaminated food/water. It presents with prolonged high fever, headache, abdominal pain, constipation/diarrhea, and rose spots. Severe cases may lead to intestinal perforation, encephalopathy, or death. Diagnosis relies on blood/stool cultures, and treatment requires antibiotics (ceftriaxone, fluoroquinolones, or azithromycin), guided by susceptibility testing due to rising antimicrobial resistance. Chronic carriers shed bacteria, necessitating prolonged antibiotic courses [1][5][9][15].
Burden
Global burden: ~9.2 million cases and 110,000 deaths annually (2019 estimates) [2][6][9].
Complications: 1–4% become chronic carriers; case fatality <1% with treatment, rising to 10–30% untreated [1][5][9].
Economic impact: Strains healthcare systems in endemic regions due to hospitalization costs and antimicrobial resistance crises [7][10][15].
Therapies
First-line antibiotics: Ceftriaxone, azithromycin, or fluoroquinolones (if susceptible) [1][5][12][16].
Resistance management: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains necessitate susceptibility testing; alternatives include high-dose azithromycin [12][16].
Carrier eradication: Prolonged antibiotic regimens (e.g., ciprofloxacin) ± cholecystectomy [1][5][9].
Categories: rare infectious diseases
Research Papers
2,653 drug discovery papers about Typhoid, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,653 drug discovery papers about Typhoid, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-04-27 | Typhoid toxin: reframing enteric fever.
SUMMARYSalmonella enterica serovars Typhi and Paratyphi A cause enteric (typhoid/paratyphoid) fever, a systemic disease that remains a major source of morbidity and mortality worldwide. The most distinctive clinical manifestations, such as sustained fever with relative bradycardia, leukopenia, neuropsychiatric symptoms/encephalopathy, and ileal perforation, have long lacked a unifying mechanistic explanation. Over the past two decades, studies of typhoid toxin have reframed how we understand this disease. Typhoid toxin is a human-adapted, chimeric A2B5 exotoxin assembled exclusively inside infected cells. It couples an ADP-ribosyltransferase (PltA) and a DNase I-like nuclease (CdtB) on a pentameric delivery ring (PltB or the alternate, PltC), that recognizes N-acetylneuraminic acid (Neu5Ac)-terminated human sialoglycans. The toxin is produced by bacteria residing within the Salmonella-containing vacuole (SCV), secreted across the bacterial envelope into the SCV lumen by a phage-derived pathway now classified as type 10 secretion system, sorted for export by the host CI-M6PR/COPII trafficking machinery, and then re-enters distant target cells via retrograde transport to the endoplasmic reticulum (ER). Recent work has linked typhoid toxin to leukopenia, blood-brain barrier disruption causing encephalopathy, gut-vascular and immune dysfunction leading to intestinal perforation, and hepatobiliary injury. The discovery of an alternate B-subunit (PltC) established a paradigm of modular B-subunit exchange that diversifies receptor usage, tissue tropism, and biology. Collectively, these insights redefine typhoid fever as a toxin-driven immunovascular disease and identify actionable targets for neutralizing antibodies and barrier-protective therapies.
2025-11-24 | Parallel Genome-Wide CRISPR Screens Reveal SORL1 and ZFYVE19 as Sequential Host Determinants of Salmonella Infection.
Salmonella enterica, a major cause of gastroenteritis and typhoid fever, hijacks host machinery to invade cells, and replicate within a specialized niche. While some host factors are known, a comprehensive, temporally-resolved understanding of the host-pathogen interface has been hindered by a lack of suitable genome-wide methodologies. To address this, a parallel CRISPR screening platform is developed to identify host determinants for distinct infection stages. An invasion screen captured factors for bacterial entry, while a fitness screen identified factors governing long-term survival. The screens reveal a temporal switch in host dependency, from endosomal trafficking in early infection to cell cycle and DNA damage response pathways governing host cell fitness in long-term infection. Notably, the approach uncovers two novel host factors with stage-specific roles, SORL1 as a mediator of bacterial invasion and ZFYVE19 as a factor supporting intracellular proliferation. Genetic disruption of SORL1 or ZFYVE19 validate these roles, leading to impaired invasion or replication, respectively. Importantly, antibody-mediated blockade of SORL1 effectively prevented Salmonella entry, highlighting it as a novel host-directed therapeutic target. Together, the screening strategy provides a powerful framework for the temporal dissection of host-pathogen interactions, revealing novel biology and promising therapeutic targets.
2025-03-27 | Helminth driven gut inflammation and microbial translocation associate with altered vaccine responses in rural Uganda.
Vaccine responses are sometimes impaired in rural, low-income settings. Helminth-associated gut barrier dysfunction and microbial translocation (MT) may be implicated. We used samples from a trial of praziquantel treatment-effects on vaccine responses in Schistosoma mansoni (Sm)-endemic Ugandan islands, measuring intestinal fatty acid-binding protein 2 (I-FABP2), lipopolysaccharide-binding protein, anti-endotoxin core antibodies (EndoCab), soluble CD14 (sCD14) in plasma, and faecal lipocalin-2, occult blood (FOB), and calprotectin (fCAL), and evaluating their associations with baseline helminth infection, praziquantel treatment, and responses to BCG, yellow fever, typhoid, HPV, and tetanus-diphtheria vaccines. Sm associated positively with fCAL and FOB, hookworm with I-FABP2, and any helminth with EndoCab IgM, fCAL and FOB. Sm associated inversely with sCD14. Praziquantel treatment reduced all marker concentrations, significantly fCAL and FOB, implying that Sm-associated gut inflammation and MT is reversible. Associations of assessed markers with vaccine-specific responses were predominantly inverse. Interventions to improve gut barrier function may enhance vaccine responsiveness.
2023-06-22 | Bacterial shedding and serologic responses following an outbreak of Salmonella Typhi in an endemic cohort.
Salmonella enterica serovar Typhi (Salmonella Typhi) is the cause of typhoid fever. Salmonella Typhi may be transmitted through shedding in the stool, which can continue after recovery from acute illness. Shedding is detected by culturing stool, which is challenging to co-ordinate at scale. We hypothesised that sero-surveillance would direct us to those shedding Salmonella Typhi in stool following a typhoid outbreak. In 2016 a typhoid outbreak affected one in four residents of a Nursing School in Malosa, Malawi. The Department of Health asked for assistance to identify nursing students that might spread the outbreak to other health facilities. We measured IgG antibody titres against Vi capsular polysaccharide (anti-Vi IgG) and IgM / IgG antibodies against H:d flagellin (anti-H:d) three and six months after the outbreak. We selected participants in the highest and lowest deciles for anti-Vi IgG titre (measured at visit one) and obtained stool for Salmonella culture and PCR. All participants reported whether they had experienced fever persisting for three days or more during the outbreak (in keeping with the WHO definitions of 'suspected typhoid'). We tested for salmonellae in the Nursing School environment. We obtained 320 paired serum samples from 407 residents. We cultured stool from 25 residents with high anti-Vi IgG titres and 24 residents with low titres. We did not recover Salmonella Typhi from stool; four stool samples yielded non-typhoidal salmonellae; one sample produced a positive PCR amplification for a Salmonella Typhi target. Median anti-Vi and anti-H:d IgG titres fell among participants who reported persistent fever. There was a smaller fall in anti-H:d IgG titres among participants who did not report persistent fever. Non-typhoidal salmonellae were identified in water sampled at source and from a kitchen tap. High titres of anti-Vi IgG did not identify culture-confirmed shedding of Salmonella Typhi. There was a clear serologic signal of recent typhoid exposure in the cohort, represented by waning IgG antibody titres over time. The presence of non-typhoidal salmonellae in drinking water indicates sub-optimal sanitation. Developing methods to detect and treat shedding remains an important priority to complement typhoid conjugate vaccination in efforts to achieve typhoid elimination.
2022-12-21 | The Lack of Natural IgM Increases Susceptibility and Impairs Anti-Vi Polysaccharide IgG Responses in a Mouse Model of Typhoid.
Circulating IgM present in the body prior to any apparent Ag exposure is referred to as natural IgM. Natural IgM provides protective immunity against a variety of pathogens. Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever in humans. Because mice are not permissive to S. Typhi infection, we employed a murine model of typhoid using S. enterica serovar Typhimurium expressing the Vi polysaccharide (ViPS) of S. Typhi (S. Typhimurium strain RC60) to evaluate the role of natural IgM in pathogenesis. We found that natural mouse IgM binds to S. Typhi and S. Typhimurium. The severity of S. Typhimurium infection in mice is dependent on presence of the natural resistance-associated macrophage protein 1 (Nramp1) allele; therefore, we infected mice deficient in secreted form of IgM (sIgM) on either a Nramp1-resistant (129S) or -susceptible (C57BL/6J) background. We found that the lack of natural IgM results in a significantly increased susceptibility and an exaggerated liver pathology regardless of the route of infection or the Nramp1 allele. Reconstitution of sIgM-/- mice with normal mouse serum or purified polyclonal IgM restored the resistance to that of sIgM+/+ mice. Furthermore, immunization of sIgM-/- mice with heat-killed S. Typhi induced a significantly reduced anti-ViPS IgG and complement-dependent bactericidal activity against S. Typhi in vitro, compared with that of sIgM+/+ mice. These findings indicate that natural IgM is an important factor in reducing the typhoid severity and inducing an optimal anti-ViPS IgG response to vaccination.
small molecules
2026-09-30 | Emergence of Genotype 2.3.1 Multidrug-Resistant Salmonella enterica Serovar Typhi Strain, West Africa, 2021-2025.
Since 2021, a genotype 2.3.1, ciprofloxacin-resistant, multidrug-resistant (MDR) Salmonella enterica serovar Typhi strain increasingly has been detected in persons returning from West Africa. This strain locally acquired 2 different MDR plasmids over a ≈25-year period, underwent chromosomal integration of the IncHI1 plasmid MDR region, and finally acquired a gyrA mutation.
2026-09-28 | Genomic Detection of Multidrug-Resistant H58 ST1 Salmonella Typhi in a South African Urban Waterway Reveals Epidemiological Links With Clinical Isolates.
Typhoid fever remains a major public health concern in South Africa. However, the role of urban waterways as environmental reservoirs and contributors to the spread of resistant Salmonella Typhi remains poorly understood. This study characterized four S. Typhi isolates recovered from the Jukskei River in Johannesburg, South Africa, using whole-genome sequencing. Genomic DNA was extracted and sequenced on the Illumina NextSeq. 2000 platform, and assembled genomes were analyzed for sequence types (STs), AMR determinants, plasmids, virulence factors, and phylogenetic relatedness using 124 clinical Salmonella genomes for comparison. All isolates were confirmed as S. Typhi, comprising ST1 (n = 2) and ST2 (n = 2). The ST1 isolates belonged to the H58 lineage (genotype 4.3.1.1), with isolate BRSA001 further classified as a sublineage 4.3.1.1. EA1. The ST1 isolates were multidrug-resistant, carrying the IncQ1 plasmid and resistant genes, including aph(6)-Id, aph(3″)-Ib, blaTEM-1B, catA1, sul1, sul2, and dfrA7. All isolates possessed mercury resistance genes (merR, merT, merP, merC), while ST1 isolates additionally harbored qacEΔ1. Ten Salmonella Pathogenicity Islands (SPI-1 to SPI-10) were identified in ST1 isolates. Phylogenetic analysis revealed notable genetic diversity among the river isolates. All river isolates clustered tightly (≤ 5 allele differences) with at least two clinical isolates, indicating shared epidemiological links and possible localized transmission. This study provides the first report of multidrug-resistant H58 S. Typhi carrying qacEΔ1 in South African surface water and highlights the Jukskei River as a potential environmental source of resistant S. Typhi, reinforcing the need for strengthened One Health genomic surveillance.
2026-09-23 | Protein-centric mechanisms of typhoidal Salmonella pathogenicity: emerging opportunities for diagnostics and anti-virulence therapeutics.
Typhoidal Salmonella (Salmonella enterica serovars Typhi and Paratyphi A) continue to impose a significant global health burden, particularly in regions characterized by inadequate sanitation and rising antimicrobial resistance. Although recent reviews have comprehensively addressed epidemiology, antimicrobial resistance, vaccination strategies, and host-pathogen interactions, virulence determinants are often described in a pathway-specific manner. Consequently, a cohesive macromolecular framework integrating these determinants remains insufficiently developed. In this review, we adopt a protein-centric perspective to systematically elucidate the molecular and structural architecture underlying typhoidal Salmonella pathogenesis. Diverse virulence determinants, including Type III Secretion System (T3SS) effectors, outer membrane proteins, adhesins, toxin subunits, stress-response regulators, and metabolic proteins, are integrated into a unified structural and functional network in which their three-dimensional architectures, protein-protein interaction interfaces, receptor-binding surfaces, catalytic domains, and active-site configurations collectively govern host-cell invasion, intracellular survival, immune evasion, nutrient acquisition, and systemic dissemination. Furthermore, we present a comparative analysis of S. Typhi and S. Paratyphi A, emphasizing differences in protein repertoires and regulatory adaptations that drive their distinct pathogenic mechanisms. Collectively, these structural insights establish a mechanistic bridge between protein architecture and pathogenic function and identify molecular interfaces, catalytic pockets, and receptor-binding surfaces as opportunities for diagnostics, vaccines, and anti-virulence therapeutics. Integration of structural biology with artificial intelligence-assisted drug discovery, protein engineering, single-cell infection models, and host-directed approaches may further accelerate the development of next-generation interventions against typhoidal Salmonella.
2026-09-14 | Haemophagocytic lymphohistiocytosis complicating typhoid fever: A case report from Senegal.
We report a case of secondary haemophagocytic lymphohistiocytosis (HLH) triggered by confirmed typhoid fever (Salmonella Typhi) in a 23-year-old Senegalese man. The initial radiological presentation suggested ileo-caecal tuberculosis. Thus, persistent fever, marked hyperferritinaemia and systemic inflammation raised suspicion of HLH, confirmed by bone marrow examination demonstrating hemophagocytosis. The H-Score was 206, corresponding to 88-93% probability. Blood cultures isolated ciprofloxacin-susceptible Salmonella Typhi. Fluoroquinolone monotherapy led to complete clinical and biological remission without the need for immunosuppression. This case underscores the importance of including typhoid fever in the differential aetiology of HLH in endemic settings, and of early H-Score calculation to expedite diagnosis.
2026-09-11 | Prolonged fever in ESBL-producing Salmonella Typhi in Lebanon: Diagnostic challenges and the possible role of occult low-level carbapenemase activity.
Salmonella Typhi remains a global health concern, particularly in travelers returning from endemic regions. We report a 32-year-old male with persistent fever after travel to Iraq. Initial investigations were inconclusive, but cultures later identified ESBL-producing S. Typhi resistant to ceftriaxone, fluoroquinolones, and TMP-SMX, but susceptible to meropenem. Fever persisted despite meropenem and resolved only after azithromycin was added. Standard testing showed no carbapenem resistance, suggesting possible undetected low-level carbapenemase activity. This case highlights the need for heightened clinical suspicion, use of advanced diagnostics, and consideration of combination therapy in prolonged typhoid fever, especially in returning travelers from high-resistance regions.
vaccines
2026-08-31 | Effectiveness of Typhoid Conjugate Vaccination in Preventing Culture-Confirmed Typhoid Fever
Objective: To compare the effectiveness of Typhoid conjugate vaccine against culture-confirmed typhoid fever. Study Design: Prospective analytical study. Place and Duration of Study: Pediatric Department, Combined Military Hospital, Abbottabad Pakistan, July 2023 to Feb 2024. Methodology: Pediatric age group patients from 2-12 years diagnosed with cases of typhoid fever were included in the study. Demographics, history of vaccination, presenting complaints, systemic exam findings, infective markers, and culture reports were recorded. Results: A total of 75 children with a diagnosis of typhoid fever were included in the study. The mean age recorded was 8.07±2.38 years with a male predominance of 54(72.0%) as compared to 21(28.0%) females. 43(57.3%) of the children were vaccinated, and the most common presenting symptom was fever in 70(93.3%) patients. Deranged platelets were the most common finding with a frequency of 54(72.0%). Negative culture was observed in 19(44.2%) vaccinated patients as compared to 03(9.4%) in unvaccinated children (p<0.01). In unvaccinated children, positive blood cultures revealed that MDR pathogen strains were most common as compared to non-resistant strains in vaccinated children. Conclusion: Vaccination against typhoid promotes significant protection against culture-proven typhoid fever. Protection against MDR strains makes typhoid vaccination a suitable choice to decrease the incidence of typhoid fever.
2026-08-21 | Development and evaluation of an indigenous Salmonella gallinarum ghost vaccine for the control of fowl typhoid in poultry.
Salmonella gallinarum, causes fowl typhoid, continues to be a significant limitation to poultry production in developing nations, with continuously rising antimicrobial resistance. The current research was design and test an indigenous S. gallinarum ghost vaccine and to measure its immunogenicity and protective effect on layer birds. Bacteriological culture of suspected clinical cases of fowl typhoid was performed, and isolates were verified by PCR against the 16S rRNA gene, after which they were sequenced, and phylogenetic analysis was performed. To obtain bacterial ghost cells, a representative native isolate was subjected to a detergent-based chemical lysis procedure, followed up by scanning electron microscopy. 120-day-old layer chicks were divided into six groups randomly and immunized at the age of seven days using oral, intramuscular, air-spray, intramuscular with oil adjuvant or eye-drop routes. There was a 1st dose at 26 days of age in all vaccinated groups and the challenge of virulent S. gallinarum at 42 and 93 days of age. ELISA was used to test humoral immune response at different time points. The highest antibody titers were found in vaccinated groups compared to controls (p < 0.05), and the intramuscular route generated the best and most enduring response in systemic immunity. Mucosal pathways elicited not high but rather significant antibody responses and provided protection against clinical disease. The research contributes to the feasibility of ghost-based vaccination in the role of a sustainable alternative to the disease control measures that are highly reliant on antibiotics in endemic poultry production systems.
2026-08-19 | Integrated genomic analysis of Salmonella Typhi from Pakistan: Antimicrobial resistance determinants, pangenome structure, and reverse vaccinology-driven vaccine target discovery.
Salmonella enterica serovar Typhi (S. Typhi) is the aetiologic agent of typhoid fever in humans. The burden of typhoid is highest in low- and middle-income countries such as Pakistan. Moreover, the increasing emergence of antibiotic-resistant and hypervirulent S. Typhi strains highlights the need for deeper genomic understanding as current treatment regimens become progressively less effective. Therefore, this study analyzed publicly available S. Typhi genomes from Pakistan to characterize genomic diversity, sequence types, plasmid content, and antimicrobial resistance and virulence profiles. Subsequently, pangenome analysis identified conserved core proteins, which were screened via reverse vaccinology to prioritize potential vaccine candidates. Analysis of 71 high-quality S. Typhi genomes identified ST-1 and ST-2 as the predominant sequence types, a finding aligned with global trends. While plasmids were detected in 32% (n = 23) of isolates, these strains exhibited significantly higher antimicrobial resistance and virulence factor gene counts compared to plasmid-free strains (p < 0.05). All isolates were found to have the aac(6')-Iaa gene. The isolates harbored Salmonella Pathogenicity Islands (SPIs), including SPI-1 through SPI-10 and SPI-12. Pangenome analysis revealed an open pangenome, with calculated pangenome size of 5912 and core genome size of 3849. Reverse vaccinology analysis prioritized three broad-spectrum S. Typhi antigens STY1784, STY1830, and STY2871 as prime vaccine candidates, with support from cross-pathogen data in the literature. Additionally, our study identified nine antigenic, strong-binding, promiscuous HLA class I epitopes. This study provides updated genomic insights into circulating S. Typhi in Pakistan and proposes novel, computationally validated vaccine targets, laying a crucial foundation for subsequent experimental investigation.
2026-08-11 | 8-year vaccine protection following a single dose of Vi-tetanus toxoid conjugate vaccine in children in Nepal (TyVOID): a prospective cohort follow-up study of the TyVAC Nepal randomised controlled trial.
In low-income and middle-income countries, where typhoid fever remains a major public health problem, WHO recommends the use of typhoid conjugate vaccine (TCV). Here, we report vaccine effectiveness up to 8 years following a single dose of TCV in Nepal. TyVOID was a prospective cohort study that extended the follow-up of children enrolled in a phase 3, double-blind, randomised controlled trial in Lalitpur, Nepal (TyVAC; Nov 20, 2017, to Oct 20, 2021). Children aged 9 months to 15 years were randomly assigned (1:1) to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) or a capsular group A meningococcal conjugate (MenA) vaccine. After unmasking and crossover vaccination, our study followed the trial participants until Oct 31, 2025. TyVAC participants who received Vi-TT were eligible for this study and categorised into either the 2017-18 cohort or 2020-21 cohort, depending on when they received the Vi-TT vaccine. The primary outcome, which was assessed in children who received both Vi-TT and MenA vaccines and with known TCV vaccination status during the government catch-up campaign in 2022, was the incidence of blood culture-confirmed typhoid identified through facility-based passive surveillance and medical record review. Adjusted incidence rate ratios (IRRs) were estimated using Poisson regression adjusted for age and sex. Vaccine effectiveness at 1-5 years and 4-8 years post-vaccination was estimated using a test-negative design among febrile children presenting to surveillance clinics, comparing odds of Vi-TT vaccination between culture-confirmed typhoid cases with negative controls. 16 131 TyVAC participants were enrolled at TyVOID baseline, of whom 14 850 provided information on Vi-CRM197 vaccination during the government catch-up campaign. After crossover and unmasking, the primary analysis population included 4941 participants vaccinated with Vi-TT in 2017-18 and 4856 participants vaccinated with Vi-TT in 2020-21. In 4856 participants in the 2020-21 Vi-TT cohort, 2402 (49·5%) were female, 2454 (50·5%) were male, and the median age at Vi-TT vaccination was 10·4 years (IQR 7·3-13·7). In 4941 participants in the 2017-18 Vi-TT cohort, 2482 (50·2%) were female, 2459 (49·8%) were male, and the median age at Vi-TT vaccination was 7·7 years (IQR 4·5-11·0). During a median follow-up of 3·7 years (3·7-3·8), the typhoid incidence rate was 111 per 100 000 person-years (95% CI 64-177) in the 2017-18 cohort and 46 per 100 000 person-years (18-94) in the 2020-21 cohort (adjusted IRR 2·41 [95% CI 1·00-5·80]; one-sided p=0·025). Vaccine effectiveness was 77% (95% CI 46-90; p=0·0006) in the 2020-21 Vi-TT cohort (1-5 years after vaccination), and 53% (8-76; p=0·027) in the 2017-18 Vi-TT cohort (4-8 years after vaccination). A single Vi-TT dose confers strong protection in the first 4 years among Nepali children, with evidence of waning by 8 years. These findings support consideration of a booster dose to sustain protection in school-age children who remain at high risk of typhoid fever. Gates Foundation and Wellcome Trust.
2026-08-09 | Cost-effectiveness and budget impact analyses of introducing typhoid conjugate vaccine into Indonesia's national immunisation program.
Typhoid fever remains a health threat in endemic countries. In Indonesia, it causes an estimated 470,000 cases and 6000 deaths annually. We assessed the cost-effectiveness and budget impact of introducing the typhoid conjugate vaccine (TCV) into Indonesia's routine National Immunisation Program (NIP) at 9 months of age, with or without a catch-up campaign up to 15 years of age. A validated dynamic model of typhoid transmission was used to project health outcomes over a 30-year analytical horison for each scenario. Cost-of-illness data were drawn from the Surveillance of Typhoid Fever in Indonesia study and published literature. Incremental cost-effectiveness ratios (ICERs) were estimated from healthcare sector and societal perspectives. Uncertainty was explored using one-way sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA). Budget impact analysis supported annual fiscal planning. Six-year budget impact costs were US$61 million (routine) and US$251 million (routine and catch-up), equivalent to 0.48%-2.95% and 2.97%-9.84% of the annual national immunisation budget, respectively. Compared to no vaccination, routine TCV yielded ICERs at US$240.6 and US$238.8 per DALY averted from the healthcare sector and societal perspectives, respectively, corresponding to 5% of GDP per capita. Compared with routine immunisation alone, adding a catch-up campaign yielded ICERs of US$521.3 and US$519.5 per DALY averted from the healthcare sector and societal perspective, respectively, corresponding to approximately 11% of GDP per capita. OWSA showed that both strategies remained very cost-effective at a willingness-to-pay threshold of 1xGDP. PSA estimated probabilities of cost-effectiveness of 99.7% (routine and catch-up vs. routine) and 99.2% (routine vs. no vaccination). The multi-strategy cost-effectiveness acceptability curve identified the combined routine and catch-up campaign as the optimal strategy. Introducing TCV into Indonesia's NIP is projected to be very cost-effective. A routine-only program requires a lower budget, but adding a catch-up campaign is an optimal strategy with greater public health impact while remaining very cost-effective. Gates Foundation grants to Murdoch Children's Research Institute in collaboration with Universitas Gadjah Mada [ref. no. INV-003867] and to TyVAC 2.0 [ref. no. INV-030857].
proteins
2026-04-13 | Typhoid Toxin of Salmonella enterica Induces ISG15 Responses Mediating Host Cell Survival and Counteracting Intracellular Infection.
The typhoid toxin is a secreted virulence factor of typhoidal serovars of the bacterial pathogen Salmonella enterica implicated in typhoid fever and chronic infections. The toxin causes a DNA damage response in human cells, characterised by cell-cycle arrest and cellular distension, resulting in cellular senescence and increased bacterial burden. To better understand host responses to typhoid toxin, we performed a transcriptomic analysis of intoxicated host cells and found that the toxin induced expression of genes relating to the type-I interferon response, including the ubiquitin-like protein ISG15. ISG15 was upregulated in a STING-dependent manner, reduced bacterial burden, and was found to be critical to host cell survival in response to the typhoid toxin and interferon. This highlights ISG15 as an important component of the host cell defence to the typhoid toxin.
2026-01-16 | A new mouse model of typhoid fever using Salmonella enterica serovar Paratyphi C as a surrogate pathogen.
Salmonella enterica serovar (S.) Typhi, the etiological agent of typhoid fever, is strictly human adapted, which presents a significant challenge for studying its pathogenesis in animal models. A common strategy to overcome this limitation is to infect mice with S. Typhimurium as a surrogate pathogen. Since S. Typhimurium is a non-typhoidal serovar that does not encode the virulence-associated capsular polysaccharide (Vi antigen) of S. Typhi, we explored whether the mouse virulent typhoidal Salmonella serovar Paratyphi C, which expresses the Vi antigen, would be better suited as a surrogate pathogen to study typhoid fever pathogenesis in the mouse. In contrast to the nontyphoidal serovar Typhimurium, which produced lethal morbidity in C57BL/6 mice within a few days after infection, S. Paratyphi C demonstrated prolonged colonization of systemic organs for up to 28 days after infection. Analysis of virulence factors revealed that the Vi antigen was important at very early stages after infection (up to 2 days), whereas the type III secretion system encoded by Salmonella pathogenicity island 2 became critical at later stages. Vaccination with purified Vi antigen suppressed S. Paratyphi C dissemination. Implantation of a biotelemetry device revealed that S. Paratyphi C triggered fever after an incubation period of 3 days, which was reminiscent of the prolonged incubation period of typhoid fever. In conclusion, our findings suggest that the use of S. Paratyphi C as a surrogate pathogen provides a mouse model for studying typhoid fever pathogenesis and vaccine development.IMPORTANCEThe emergence of extensively drug-resistant Salmonella enterica serovar (S.) Typhi poses a serious threat to public health, but its host restriction to humans poses a challenge for studying pathogenesis and vaccine development in animal models. Here, we used S. Paratyphi C, a mouse virulent typhoidal serovar that expresses the virulence-associated Vi capsular polysaccharide, as a surrogate pathogen for studying typhoid fever in a mouse model. Our model recapitulates key features of typhoid fever, including clinical symptoms such as a prolonged incubation period, fever, and splenomegaly. Notably, disseminated infection with S. Paratyphi C developed after inoculation by the natural oral route. We demonstrate the utility of this model for studying pathogenesis and vaccination. We conclude that our new mouse model for typhoid fever offers a promising platform for evaluating novel therapeutics and vaccine candidates to address the problem of drug resistance in S. Typhi and reduce the global burden of typhoid fever.
2025-10-29 | Lacticaseibacillus rhamnosus D1 Fermented Milk Confers Protection Against Typhoid Fever Through Immunomodulation and Gut Microbiota Regulation in Mice.
This study investigated the protective effect of fermented milk by Lacticaseibacillus rhamnosus D1 in a murine model of Typhoid fever, focusing on cytokines, antimicrobial peptides and microbiota modulation. BALB/c mice were pre-treated with milk fermented by L. rhamnosus D1 prior to Salmonella Typhimurium challenge. Outcomes assessed included survival, weight change, bacterial translocation, mRNA expression of cytokines and antimicrobial peptides, in addition to gut microbiota modulation. Mice receiving fermented milk exhibited higher survival rates, reduced bacterial translocation and attenuated weight loss compared to controls. mRNA expression analyses revealed that L. rhamnosus D1 pre-treatment suppressed the expression of pro-inflammatory cytokines (IFN-γ, IL-6 and IL-12) and upregulated anti-inflammatory cytokines (IL-5, IL-10 and TGF-β), as well as antimicrobial peptides (Reg3β, Reg3γ and Lcn2). Furthermore, we observed that the consumption of fermented milk changed the gut microbiota of infected mice, not only by modulating the existing taxa, but also by facilitating the emergence of unique, potentially beneficial microbial lineages, such as Muribaculum, Roseburia, Intestinimonas, Bdellovibrio and Facklamia. These findings indicate that L. rhamnosus D1 protected mice against S. Typhimurium infection through immunomodulatory and microbiota-mediated mechanisms, changing mucosal immunity and strengthening the intestinal barrier by modulating gut microbiota and immune responses, in addition to promoting host antimicrobial defenses.
2025-09-22 | FliC adjuvant augments protective efficacy of recombinant T2544 antigen against SalmonellaTyphiand Paratyphi A by increasing serum antibodies, intestinal secretory immunoglobulin A and T cell memory.
The need for safe, effective, and affordable vaccines against Salmonella Typhi and Paratyphi A remains urgent, particularly in endemic regions of Asia and Africa. Contrary to earlier beliefs, parenteral vaccines can induce mucosal immunity, especially when combined with mucosal trafficking signals. Recent findings show that systemic delivery of soluble flagellin (FliC) activates CD103+ dendritic cells via TLR5, promoting mucosal IgA and regulatory T cell responses. Building on this, we evaluated recombinant FliC (rFliC) from S. Typhimurium as an adjuvant to enhance both systemic and mucosal immunity of rT2544, a subunit vaccine candidate. Female BALB/c mice were immunized subcutaneously with varying doses of rT2544 and rFliC to identify an optimal formulation. The selected dose (5 μg rT2544 + 2.5 μg rFliC) was tested for humoral and cellular responses, including serum IgG/IgA titers, antibody-secreting cells, cytokines (IFN-γ, IL-4, IL-17), and CTL activity. Protective efficacy was evaluated in an iron-overload mouse model challenged with S. Typhiand S. Paratyphi A, by assessing survival and bacterial loads in the intestine, liver, and spleen. Co-administration of rFliC with rT2544 enhanced systemic IgG and intestinal IgA responses, with increased ASCs and strong bactericidal activity against S. Typhiand S. Paratyphi A. The vaccine induced robust Th1, Th2, and Th17 cytokines, and improved CTL activity. Immunized mice showed 83 % and 91 % survival against S. Typhiand S. Paratyphi A, respectively, with significantly reduced bacterial loads in the intestine, liver, and spleen. Importantly, subcutaneous rFliC delivery effectively induced intestinal sIgA, eliminating the need for mucosal administration. Subcutaneous co-administration of rFliC induced strong antigen-specific mucosal sIgA, overcoming limitations of conventional mucosal adjuvants. The rFliC-adjuvanted rT2544 elicited robust humoral, mucosal, and cellular responses, providing significant protection against S. Typhiand S. Paratyphi A. These findings support its potential as a promising injectable subunit vaccine for enteric fever.
2025-07-23 | Salmonella Typhi gut invasion drives hypoxic immune subsets associated with disease outcomes.
Salmonella Typhi (S. Typhi), the causative agent of typhoid disease, remains a major public health concern. Owing to the human-restricted nature of S. Typhi, studies of typhoid pathogenesis in animal models are limited to a murine non-typhoidal pathogen. More recently, human challenge models have been conducted, providing insight into immune correlates of infection outcomes, which are still incompletely understood. Here, we performed an integrated single-cell analysis of immune responses from the human S. Typhi challenge model and mouse model of typhoid disease, to associate biological mechanism with human infection outcome. Most prominent, we revealed immune subsets with a hypoxia-related signature in the blood of individuals who developed disease in the human challenge model. This signature was also evident in the mouse model in activated macrophages infiltrating into the Peyer's patches, but not during infection with a mutant strain impaired for gut invasion. We further identified hypoxia-related signature as a general immune correlate of disease outcome in other infection-and inflammatory-related diseases. Collectively, we identified a hypoxia-associated immune signature that correlates with disease outcomes in humans. Using a mouse model, we demonstrated that this signature is driven by bacterial invasion to the Peyer's patches, implicating a causal role in the pathogenesis of typhoid fever.
other
2026-09-23 | Impaired acid stress resistance in Salmonella Typhi Ty2.
Salmonella enterica encounters acid stress during gastrointestinal transit and within the phagosomal environment of macrophages. Acid stress resistance has been well characterized in Salmonella enterica serovar Typhimurium, but comparative studies in the human-adapted Salmonella enterica serovar Typhi are limited. We compared the growth of S. Typhimurium 14028s and S. Typhi Ty2 at pH values ranging from 3 to 8 and observed that Salmonella enterica serovar Typhimurium exhibits enhanced growth at pH 4.5 compared to S. Typhi. Comparative transcriptomic profiling of S. Typhimurium and S. Typhi at pH 4.5 and 7.5 identified numerous differentially expressed acid-induced genes (DEGs), including genes encoding membrane proteins (OmpC, PhoE, HydB), a transcriptional regulator (RpoS), and stress response proteins (YciG, STM14_1829, YmdF). Targeted deletion of selected genes in S. Typhimurium significantly suppressed growth at acidic pH, confirming their role in acid stress resistance. These resistance mechanisms are compromised in S. Typhi due to pseudogenization. Heterologous expression of pseudogenized genes in S. Typhi restored acid tolerance. Collectively, these findings suggest that S. Typhi has lost the ability to withstand acid stress due to genomic decay and the loss of multiple genes essential for acid survival in S. Typhimurium, reflecting divergent evolutionary paths in these two serovars. Salmonella Typhimurium must adapt to acidic pH conditions in the intestinal tract and the intracellular environment to cause infection. In this study, we show that the enteric fever serovar Salmonella Typhi exhibits impaired growth at pH 4.5 in comparison to Salmonella Typhimurium. We further show that the loss of specific membrane proteins, a transcriptional regulator, and a family of stress response proteins in Salmonella Typhi are responsible for this difference. Collectively, these observations suggest that Salmonella Typhi has evolutionarily lost the ability to withstand acid stress due to differences in its interaction with the human host. This has important implications for the pathogenesis of typhoid fever.
2026-05-04 | Advancing Needle-Free Jet Injectors for Global Vaccine Delivery.
Background: Global immunization programs continue to rely on needle-based injections despite persistent concerns regarding sharps disposal, accidental injuries, and the technical skill required for accurate intradermal administration. Needle-free jet injectors (NFJIs) are an alternative delivery method in which narrow, high-velocity liquid jets penetrate the skin without a needle. Contemporary designs, ranging from single-use disposable-syringe injectors to digitally controlled electromechanical devices, address historical safety issues and meet current WHO and FDA device expectations. Methods: Evidence from engineering analyses, preclinical modeling, and clinical trials was reviewed to characterize how jet velocity, nozzle structure, and formulation rheology influence skin penetration and drug dispersion. Published vaccine studies were examined for antibody responses, seroconversion, and reactogenicity compared with needle-syringe injection. Field vaccination campaign data from national campaigns and operational reports were evaluated to describe implementation steps, acceptability, and implementation constraints. Results: Published studies evaluating vaccines, including inactivated influenza, hepatitis B, typhoid, rabies, and measles, report antibody titers and seroconversion rates after NFJI administration that are comparable to those achieved with conventional intramuscular or intradermal needle injection. Needle-free delivery was associated with operational advantages in several immunization programs, including reduced sharps waste and improved vaccination rate during high-volume immunization campaigns. Local and systemic reactogenicity follows expected patterns, with slightly higher injection-site responses in some NFJI studies. Imaging and mechanical data confirm that jet performance depends on nozzle geometry and controlled pressure pulses. At the same time, formulation stability remains a critical determinant of successful jet-based vaccine administration, particularly for protein antigens, adjuvanted formulations, and emerging mRNA vaccines that may experience transient shear stress during high-velocity injection. Evidence from vaccination campaigns further indicates that needle-free jet injectors reduce sharps waste, simplify vaccine handling and administration procedures, and support rapid vaccine delivery in large-scale immunization programs. Conclusions: Needle-free jet injectors are a practical alternative to traditional needle-based injections for some vaccines. Their main benefits include enabling intradermal dose-sparing strategies, reducing reliance on sharps disposal methods, and enabling the efficient vaccination of large groups without compromising immunogenicity. Future research should define the physicochemical stability limits of biologic formulations subjected to jet injection and evaluate digitally controlled injectors capable of precise pressure modulation and adjustable delivery parameters. In addition, needle-free jet injection eliminates needle penetration and sharps handling, which may reduce needle-associated anxiety and improve vaccine acceptability among individuals with needle aversion.
2024-09-07 | Oral Treatment with Saccharomyces cerevisiae CNCM I-3856 Mitigates the Inflammatory Response Experimentally Induced by Salmonella enterica subsp. enterica Serovar Typhimurium in Mice.
Salmonella spp. are intracellular, Gram-negative pathogens responsible for a range of diarrheal diseases, which can present either as self-limited (gastroenteritis) or as a systemic form (typhoid fever), characterizing a serious public health problem. In this study, we investigated the therapeutic effects of oral administration of Saccharomyces cerevisiae CNCM I-3856 in a murine model infected with Salmonella Typhimurium (ST). This yeast species has previously demonstrated the potential to support immune function and reduce inflammation and the ability to exert antimicrobial activity, which is important considering the increasing prevalence of antibiotic-resistant bacteria. Our findings revealed that mice infected with ST and only treated with sterile saline exhibited a higher mortality rate and body weight loss. In contrast, mice treated with I-3856 showed a notable reduction in these adverse outcomes. The yeast demonstrated a high capacity for co-aggregation with the pathogen. Furthermore, the significant amounts of yeast found in the feces of treated mice suggest that intestinal colonization was effective, which was associated with several beneficial effects, including reduced intestinal permeability, which likely limits bacterial translocation to extraintestinal organs. Additionally, the administration of I-3856 reduced levels of sIgA and resulted in a decrease in the recruitment of neutrophils and eosinophils to infection sites, indicating a modulation of the inflammatory response. Histological analyses showed attenuated liver and intestinal lesions in the yeast-treated mice, corroborating the protective effects of the yeast. In conclusion, the results suggest that S. cerevisiae CNCM I-3856 has the potential to control the inflammatory response experimentally induced by S. Typhimurium when administered to mice.
2023-11-29 | Deletion of Salmonella enterica serovar Typhi tolC reduces bacterial adhesion and invasion toward host cells.
S. Typhi is a Gram-negative bacterium that causes typhoid fever in humans. Its virulence depends on the TolC outer membrane pump, which expels toxic compounds and antibiotics. However, the role of TolC in the host cell adhesion and invasion by S. Typhi is unclear. We aimed to investigate how deleting the tolC affects the adhesion and invasion of HT-29 epithelial and THP-1 macrophage cells by S. Typhi in vitro. We compared the adhesion and invasion rates of the wild-type and the tolC mutant strains of S. Typhi using in vitro adhesion and invasion assays. We also measured the expression levels of SPI-1 genes (invF, sipA, sipC, and sipD) using quantitative PCR. We found that the tolC mutant showed a significant reduction in adhesion and invasion compared to the wild-type strain in both cell types. We also observed that the expression of SPI-1 genes was downregulated in the tolC mutant. Our results suggest that TolC modulates the expression of SPI-1 genes and facilitates the adhesion and invasion of host cells by S. Typhi. Our study provides new insights into the molecular mechanisms of S. Typhi pathogenesis and antibiotic resistance. However, our study is limited by the use of in vitro models and does not reflect the complex interactions between S. Typhi and host cells in vivo.
2023-01-11 | Identification of collaborative cross mouse strains permissive to Salmonella enterica serovar Typhi infection.
Salmonella enterica serovar Typhi is the causative agent of typhoid fever restricted to humans and does not replicate in commonly used inbred mice. Genetic variation in humans is far greater and more complex than that in a single inbred strain of mice. The Collaborative Cross (CC) is a large panel of recombinant inbred strains which has a wider range of genetic diversity than laboratory inbred mouse strains. We found that the CC003/Unc and CC053/Unc strains are permissive to intraperitoneal but not oral route of S. Typhi infection and show histopathological changes characteristic of human typhoid. These CC strains are immunocompetent, and immunization induces antigen-specific responses that can kill S. Typhi in vitro and control S. Typhi in vivo. Our results indicate that CC003/Unc and CC053/Unc strains can help identify the genetic basis for typhoid susceptibility, S. Typhi virulence mechanism(s) in vivo, and serve as a preclinical mammalian model system to identify effective vaccines and therapeutics strategies.
antibodies
2026-04-27 | Typhoid toxin: reframing enteric fever.
SUMMARYSalmonella enterica serovars Typhi and Paratyphi A cause enteric (typhoid/paratyphoid) fever, a systemic disease that remains a major source of morbidity and mortality worldwide. The most distinctive clinical manifestations, such as sustained fever with relative bradycardia, leukopenia, neuropsychiatric symptoms/encephalopathy, and ileal perforation, have long lacked a unifying mechanistic explanation. Over the past two decades, studies of typhoid toxin have reframed how we understand this disease. Typhoid toxin is a human-adapted, chimeric A2B5 exotoxin assembled exclusively inside infected cells. It couples an ADP-ribosyltransferase (PltA) and a DNase I-like nuclease (CdtB) on a pentameric delivery ring (PltB or the alternate, PltC), that recognizes N-acetylneuraminic acid (Neu5Ac)-terminated human sialoglycans. The toxin is produced by bacteria residing within the Salmonella-containing vacuole (SCV), secreted across the bacterial envelope into the SCV lumen by a phage-derived pathway now classified as type 10 secretion system, sorted for export by the host CI-M6PR/COPII trafficking machinery, and then re-enters distant target cells via retrograde transport to the endoplasmic reticulum (ER). Recent work has linked typhoid toxin to leukopenia, blood-brain barrier disruption causing encephalopathy, gut-vascular and immune dysfunction leading to intestinal perforation, and hepatobiliary injury. The discovery of an alternate B-subunit (PltC) established a paradigm of modular B-subunit exchange that diversifies receptor usage, tissue tropism, and biology. Collectively, these insights redefine typhoid fever as a toxin-driven immunovascular disease and identify actionable targets for neutralizing antibodies and barrier-protective therapies.
2025-11-24 | Parallel Genome-Wide CRISPR Screens Reveal SORL1 and ZFYVE19 as Sequential Host Determinants of Salmonella Infection.
Salmonella enterica, a major cause of gastroenteritis and typhoid fever, hijacks host machinery to invade cells, and replicate within a specialized niche. While some host factors are known, a comprehensive, temporally-resolved understanding of the host-pathogen interface has been hindered by a lack of suitable genome-wide methodologies. To address this, a parallel CRISPR screening platform is developed to identify host determinants for distinct infection stages. An invasion screen captured factors for bacterial entry, while a fitness screen identified factors governing long-term survival. The screens reveal a temporal switch in host dependency, from endosomal trafficking in early infection to cell cycle and DNA damage response pathways governing host cell fitness in long-term infection. Notably, the approach uncovers two novel host factors with stage-specific roles, SORL1 as a mediator of bacterial invasion and ZFYVE19 as a factor supporting intracellular proliferation. Genetic disruption of SORL1 or ZFYVE19 validate these roles, leading to impaired invasion or replication, respectively. Importantly, antibody-mediated blockade of SORL1 effectively prevented Salmonella entry, highlighting it as a novel host-directed therapeutic target. Together, the screening strategy provides a powerful framework for the temporal dissection of host-pathogen interactions, revealing novel biology and promising therapeutic targets.
2025-03-27 | Helminth driven gut inflammation and microbial translocation associate with altered vaccine responses in rural Uganda.
Vaccine responses are sometimes impaired in rural, low-income settings. Helminth-associated gut barrier dysfunction and microbial translocation (MT) may be implicated. We used samples from a trial of praziquantel treatment-effects on vaccine responses in Schistosoma mansoni (Sm)-endemic Ugandan islands, measuring intestinal fatty acid-binding protein 2 (I-FABP2), lipopolysaccharide-binding protein, anti-endotoxin core antibodies (EndoCab), soluble CD14 (sCD14) in plasma, and faecal lipocalin-2, occult blood (FOB), and calprotectin (fCAL), and evaluating their associations with baseline helminth infection, praziquantel treatment, and responses to BCG, yellow fever, typhoid, HPV, and tetanus-diphtheria vaccines. Sm associated positively with fCAL and FOB, hookworm with I-FABP2, and any helminth with EndoCab IgM, fCAL and FOB. Sm associated inversely with sCD14. Praziquantel treatment reduced all marker concentrations, significantly fCAL and FOB, implying that Sm-associated gut inflammation and MT is reversible. Associations of assessed markers with vaccine-specific responses were predominantly inverse. Interventions to improve gut barrier function may enhance vaccine responsiveness.
2023-06-22 | Bacterial shedding and serologic responses following an outbreak of Salmonella Typhi in an endemic cohort.
Salmonella enterica serovar Typhi (Salmonella Typhi) is the cause of typhoid fever. Salmonella Typhi may be transmitted through shedding in the stool, which can continue after recovery from acute illness. Shedding is detected by culturing stool, which is challenging to co-ordinate at scale. We hypothesised that sero-surveillance would direct us to those shedding Salmonella Typhi in stool following a typhoid outbreak. In 2016 a typhoid outbreak affected one in four residents of a Nursing School in Malosa, Malawi. The Department of Health asked for assistance to identify nursing students that might spread the outbreak to other health facilities. We measured IgG antibody titres against Vi capsular polysaccharide (anti-Vi IgG) and IgM / IgG antibodies against H:d flagellin (anti-H:d) three and six months after the outbreak. We selected participants in the highest and lowest deciles for anti-Vi IgG titre (measured at visit one) and obtained stool for Salmonella culture and PCR. All participants reported whether they had experienced fever persisting for three days or more during the outbreak (in keeping with the WHO definitions of 'suspected typhoid'). We tested for salmonellae in the Nursing School environment. We obtained 320 paired serum samples from 407 residents. We cultured stool from 25 residents with high anti-Vi IgG titres and 24 residents with low titres. We did not recover Salmonella Typhi from stool; four stool samples yielded non-typhoidal salmonellae; one sample produced a positive PCR amplification for a Salmonella Typhi target. Median anti-Vi and anti-H:d IgG titres fell among participants who reported persistent fever. There was a smaller fall in anti-H:d IgG titres among participants who did not report persistent fever. Non-typhoidal salmonellae were identified in water sampled at source and from a kitchen tap. High titres of anti-Vi IgG did not identify culture-confirmed shedding of Salmonella Typhi. There was a clear serologic signal of recent typhoid exposure in the cohort, represented by waning IgG antibody titres over time. The presence of non-typhoidal salmonellae in drinking water indicates sub-optimal sanitation. Developing methods to detect and treat shedding remains an important priority to complement typhoid conjugate vaccination in efforts to achieve typhoid elimination.
2022-12-21 | The Lack of Natural IgM Increases Susceptibility and Impairs Anti-Vi Polysaccharide IgG Responses in a Mouse Model of Typhoid.
Circulating IgM present in the body prior to any apparent Ag exposure is referred to as natural IgM. Natural IgM provides protective immunity against a variety of pathogens. Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever in humans. Because mice are not permissive to S. Typhi infection, we employed a murine model of typhoid using S. enterica serovar Typhimurium expressing the Vi polysaccharide (ViPS) of S. Typhi (S. Typhimurium strain RC60) to evaluate the role of natural IgM in pathogenesis. We found that natural mouse IgM binds to S. Typhi and S. Typhimurium. The severity of S. Typhimurium infection in mice is dependent on presence of the natural resistance-associated macrophage protein 1 (Nramp1) allele; therefore, we infected mice deficient in secreted form of IgM (sIgM) on either a Nramp1-resistant (129S) or -susceptible (C57BL/6J) background. We found that the lack of natural IgM results in a significantly increased susceptibility and an exaggerated liver pathology regardless of the route of infection or the Nramp1 allele. Reconstitution of sIgM-/- mice with normal mouse serum or purified polyclonal IgM restored the resistance to that of sIgM+/+ mice. Furthermore, immunization of sIgM-/- mice with heat-killed S. Typhi induced a significantly reduced anti-ViPS IgG and complement-dependent bactericidal activity against S. Typhi in vitro, compared with that of sIgM+/+ mice. These findings indicate that natural IgM is an important factor in reducing the typhoid severity and inducing an optimal anti-ViPS IgG response to vaccination.
small molecules
2026-09-30 | Emergence of Genotype 2.3.1 Multidrug-Resistant Salmonella enterica Serovar Typhi Strain, West Africa, 2021-2025.
Since 2021, a genotype 2.3.1, ciprofloxacin-resistant, multidrug-resistant (MDR) Salmonella enterica serovar Typhi strain increasingly has been detected in persons returning from West Africa. This strain locally acquired 2 different MDR plasmids over a ≈25-year period, underwent chromosomal integration of the IncHI1 plasmid MDR region, and finally acquired a gyrA mutation.
2026-09-28 | Genomic Detection of Multidrug-Resistant H58 ST1 Salmonella Typhi in a South African Urban Waterway Reveals Epidemiological Links With Clinical Isolates.
Typhoid fever remains a major public health concern in South Africa. However, the role of urban waterways as environmental reservoirs and contributors to the spread of resistant Salmonella Typhi remains poorly understood. This study characterized four S. Typhi isolates recovered from the Jukskei River in Johannesburg, South Africa, using whole-genome sequencing. Genomic DNA was extracted and sequenced on the Illumina NextSeq. 2000 platform, and assembled genomes were analyzed for sequence types (STs), AMR determinants, plasmids, virulence factors, and phylogenetic relatedness using 124 clinical Salmonella genomes for comparison. All isolates were confirmed as S. Typhi, comprising ST1 (n = 2) and ST2 (n = 2). The ST1 isolates belonged to the H58 lineage (genotype 4.3.1.1), with isolate BRSA001 further classified as a sublineage 4.3.1.1. EA1. The ST1 isolates were multidrug-resistant, carrying the IncQ1 plasmid and resistant genes, including aph(6)-Id, aph(3″)-Ib, blaTEM-1B, catA1, sul1, sul2, and dfrA7. All isolates possessed mercury resistance genes (merR, merT, merP, merC), while ST1 isolates additionally harbored qacEΔ1. Ten Salmonella Pathogenicity Islands (SPI-1 to SPI-10) were identified in ST1 isolates. Phylogenetic analysis revealed notable genetic diversity among the river isolates. All river isolates clustered tightly (≤ 5 allele differences) with at least two clinical isolates, indicating shared epidemiological links and possible localized transmission. This study provides the first report of multidrug-resistant H58 S. Typhi carrying qacEΔ1 in South African surface water and highlights the Jukskei River as a potential environmental source of resistant S. Typhi, reinforcing the need for strengthened One Health genomic surveillance.
2026-09-23 | Protein-centric mechanisms of typhoidal Salmonella pathogenicity: emerging opportunities for diagnostics and anti-virulence therapeutics.
Typhoidal Salmonella (Salmonella enterica serovars Typhi and Paratyphi A) continue to impose a significant global health burden, particularly in regions characterized by inadequate sanitation and rising antimicrobial resistance. Although recent reviews have comprehensively addressed epidemiology, antimicrobial resistance, vaccination strategies, and host-pathogen interactions, virulence determinants are often described in a pathway-specific manner. Consequently, a cohesive macromolecular framework integrating these determinants remains insufficiently developed. In this review, we adopt a protein-centric perspective to systematically elucidate the molecular and structural architecture underlying typhoidal Salmonella pathogenesis. Diverse virulence determinants, including Type III Secretion System (T3SS) effectors, outer membrane proteins, adhesins, toxin subunits, stress-response regulators, and metabolic proteins, are integrated into a unified structural and functional network in which their three-dimensional architectures, protein-protein interaction interfaces, receptor-binding surfaces, catalytic domains, and active-site configurations collectively govern host-cell invasion, intracellular survival, immune evasion, nutrient acquisition, and systemic dissemination. Furthermore, we present a comparative analysis of S. Typhi and S. Paratyphi A, emphasizing differences in protein repertoires and regulatory adaptations that drive their distinct pathogenic mechanisms. Collectively, these structural insights establish a mechanistic bridge between protein architecture and pathogenic function and identify molecular interfaces, catalytic pockets, and receptor-binding surfaces as opportunities for diagnostics, vaccines, and anti-virulence therapeutics. Integration of structural biology with artificial intelligence-assisted drug discovery, protein engineering, single-cell infection models, and host-directed approaches may further accelerate the development of next-generation interventions against typhoidal Salmonella.
2026-09-14 | Haemophagocytic lymphohistiocytosis complicating typhoid fever: A case report from Senegal.
We report a case of secondary haemophagocytic lymphohistiocytosis (HLH) triggered by confirmed typhoid fever (Salmonella Typhi) in a 23-year-old Senegalese man. The initial radiological presentation suggested ileo-caecal tuberculosis. Thus, persistent fever, marked hyperferritinaemia and systemic inflammation raised suspicion of HLH, confirmed by bone marrow examination demonstrating hemophagocytosis. The H-Score was 206, corresponding to 88-93% probability. Blood cultures isolated ciprofloxacin-susceptible Salmonella Typhi. Fluoroquinolone monotherapy led to complete clinical and biological remission without the need for immunosuppression. This case underscores the importance of including typhoid fever in the differential aetiology of HLH in endemic settings, and of early H-Score calculation to expedite diagnosis.
2026-09-11 | Prolonged fever in ESBL-producing Salmonella Typhi in Lebanon: Diagnostic challenges and the possible role of occult low-level carbapenemase activity.
Salmonella Typhi remains a global health concern, particularly in travelers returning from endemic regions. We report a 32-year-old male with persistent fever after travel to Iraq. Initial investigations were inconclusive, but cultures later identified ESBL-producing S. Typhi resistant to ceftriaxone, fluoroquinolones, and TMP-SMX, but susceptible to meropenem. Fever persisted despite meropenem and resolved only after azithromycin was added. Standard testing showed no carbapenem resistance, suggesting possible undetected low-level carbapenemase activity. This case highlights the need for heightened clinical suspicion, use of advanced diagnostics, and consideration of combination therapy in prolonged typhoid fever, especially in returning travelers from high-resistance regions.
vaccines
2026-08-31 | Effectiveness of Typhoid Conjugate Vaccination in Preventing Culture-Confirmed Typhoid Fever
Objective: To compare the effectiveness of Typhoid conjugate vaccine against culture-confirmed typhoid fever. Study Design: Prospective analytical study. Place and Duration of Study: Pediatric Department, Combined Military Hospital, Abbottabad Pakistan, July 2023 to Feb 2024. Methodology: Pediatric age group patients from 2-12 years diagnosed with cases of typhoid fever were included in the study. Demographics, history of vaccination, presenting complaints, systemic exam findings, infective markers, and culture reports were recorded. Results: A total of 75 children with a diagnosis of typhoid fever were included in the study. The mean age recorded was 8.07±2.38 years with a male predominance of 54(72.0%) as compared to 21(28.0%) females. 43(57.3%) of the children were vaccinated, and the most common presenting symptom was fever in 70(93.3%) patients. Deranged platelets were the most common finding with a frequency of 54(72.0%). Negative culture was observed in 19(44.2%) vaccinated patients as compared to 03(9.4%) in unvaccinated children (p<0.01). In unvaccinated children, positive blood cultures revealed that MDR pathogen strains were most common as compared to non-resistant strains in vaccinated children. Conclusion: Vaccination against typhoid promotes significant protection against culture-proven typhoid fever. Protection against MDR strains makes typhoid vaccination a suitable choice to decrease the incidence of typhoid fever.
2026-08-21 | Development and evaluation of an indigenous Salmonella gallinarum ghost vaccine for the control of fowl typhoid in poultry.
Salmonella gallinarum, causes fowl typhoid, continues to be a significant limitation to poultry production in developing nations, with continuously rising antimicrobial resistance. The current research was design and test an indigenous S. gallinarum ghost vaccine and to measure its immunogenicity and protective effect on layer birds. Bacteriological culture of suspected clinical cases of fowl typhoid was performed, and isolates were verified by PCR against the 16S rRNA gene, after which they were sequenced, and phylogenetic analysis was performed. To obtain bacterial ghost cells, a representative native isolate was subjected to a detergent-based chemical lysis procedure, followed up by scanning electron microscopy. 120-day-old layer chicks were divided into six groups randomly and immunized at the age of seven days using oral, intramuscular, air-spray, intramuscular with oil adjuvant or eye-drop routes. There was a 1st dose at 26 days of age in all vaccinated groups and the challenge of virulent S. gallinarum at 42 and 93 days of age. ELISA was used to test humoral immune response at different time points. The highest antibody titers were found in vaccinated groups compared to controls (p < 0.05), and the intramuscular route generated the best and most enduring response in systemic immunity. Mucosal pathways elicited not high but rather significant antibody responses and provided protection against clinical disease. The research contributes to the feasibility of ghost-based vaccination in the role of a sustainable alternative to the disease control measures that are highly reliant on antibiotics in endemic poultry production systems.
2026-08-19 | Integrated genomic analysis of Salmonella Typhi from Pakistan: Antimicrobial resistance determinants, pangenome structure, and reverse vaccinology-driven vaccine target discovery.
Salmonella enterica serovar Typhi (S. Typhi) is the aetiologic agent of typhoid fever in humans. The burden of typhoid is highest in low- and middle-income countries such as Pakistan. Moreover, the increasing emergence of antibiotic-resistant and hypervirulent S. Typhi strains highlights the need for deeper genomic understanding as current treatment regimens become progressively less effective. Therefore, this study analyzed publicly available S. Typhi genomes from Pakistan to characterize genomic diversity, sequence types, plasmid content, and antimicrobial resistance and virulence profiles. Subsequently, pangenome analysis identified conserved core proteins, which were screened via reverse vaccinology to prioritize potential vaccine candidates. Analysis of 71 high-quality S. Typhi genomes identified ST-1 and ST-2 as the predominant sequence types, a finding aligned with global trends. While plasmids were detected in 32% (n = 23) of isolates, these strains exhibited significantly higher antimicrobial resistance and virulence factor gene counts compared to plasmid-free strains (p < 0.05). All isolates were found to have the aac(6')-Iaa gene. The isolates harbored Salmonella Pathogenicity Islands (SPIs), including SPI-1 through SPI-10 and SPI-12. Pangenome analysis revealed an open pangenome, with calculated pangenome size of 5912 and core genome size of 3849. Reverse vaccinology analysis prioritized three broad-spectrum S. Typhi antigens STY1784, STY1830, and STY2871 as prime vaccine candidates, with support from cross-pathogen data in the literature. Additionally, our study identified nine antigenic, strong-binding, promiscuous HLA class I epitopes. This study provides updated genomic insights into circulating S. Typhi in Pakistan and proposes novel, computationally validated vaccine targets, laying a crucial foundation for subsequent experimental investigation.
2026-08-11 | 8-year vaccine protection following a single dose of Vi-tetanus toxoid conjugate vaccine in children in Nepal (TyVOID): a prospective cohort follow-up study of the TyVAC Nepal randomised controlled trial.
In low-income and middle-income countries, where typhoid fever remains a major public health problem, WHO recommends the use of typhoid conjugate vaccine (TCV). Here, we report vaccine effectiveness up to 8 years following a single dose of TCV in Nepal. TyVOID was a prospective cohort study that extended the follow-up of children enrolled in a phase 3, double-blind, randomised controlled trial in Lalitpur, Nepal (TyVAC; Nov 20, 2017, to Oct 20, 2021). Children aged 9 months to 15 years were randomly assigned (1:1) to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) or a capsular group A meningococcal conjugate (MenA) vaccine. After unmasking and crossover vaccination, our study followed the trial participants until Oct 31, 2025. TyVAC participants who received Vi-TT were eligible for this study and categorised into either the 2017-18 cohort or 2020-21 cohort, depending on when they received the Vi-TT vaccine. The primary outcome, which was assessed in children who received both Vi-TT and MenA vaccines and with known TCV vaccination status during the government catch-up campaign in 2022, was the incidence of blood culture-confirmed typhoid identified through facility-based passive surveillance and medical record review. Adjusted incidence rate ratios (IRRs) were estimated using Poisson regression adjusted for age and sex. Vaccine effectiveness at 1-5 years and 4-8 years post-vaccination was estimated using a test-negative design among febrile children presenting to surveillance clinics, comparing odds of Vi-TT vaccination between culture-confirmed typhoid cases with negative controls. 16 131 TyVAC participants were enrolled at TyVOID baseline, of whom 14 850 provided information on Vi-CRM197 vaccination during the government catch-up campaign. After crossover and unmasking, the primary analysis population included 4941 participants vaccinated with Vi-TT in 2017-18 and 4856 participants vaccinated with Vi-TT in 2020-21. In 4856 participants in the 2020-21 Vi-TT cohort, 2402 (49·5%) were female, 2454 (50·5%) were male, and the median age at Vi-TT vaccination was 10·4 years (IQR 7·3-13·7). In 4941 participants in the 2017-18 Vi-TT cohort, 2482 (50·2%) were female, 2459 (49·8%) were male, and the median age at Vi-TT vaccination was 7·7 years (IQR 4·5-11·0). During a median follow-up of 3·7 years (3·7-3·8), the typhoid incidence rate was 111 per 100 000 person-years (95% CI 64-177) in the 2017-18 cohort and 46 per 100 000 person-years (18-94) in the 2020-21 cohort (adjusted IRR 2·41 [95% CI 1·00-5·80]; one-sided p=0·025). Vaccine effectiveness was 77% (95% CI 46-90; p=0·0006) in the 2020-21 Vi-TT cohort (1-5 years after vaccination), and 53% (8-76; p=0·027) in the 2017-18 Vi-TT cohort (4-8 years after vaccination). A single Vi-TT dose confers strong protection in the first 4 years among Nepali children, with evidence of waning by 8 years. These findings support consideration of a booster dose to sustain protection in school-age children who remain at high risk of typhoid fever. Gates Foundation and Wellcome Trust.
2026-08-09 | Cost-effectiveness and budget impact analyses of introducing typhoid conjugate vaccine into Indonesia's national immunisation program.
Typhoid fever remains a health threat in endemic countries. In Indonesia, it causes an estimated 470,000 cases and 6000 deaths annually. We assessed the cost-effectiveness and budget impact of introducing the typhoid conjugate vaccine (TCV) into Indonesia's routine National Immunisation Program (NIP) at 9 months of age, with or without a catch-up campaign up to 15 years of age. A validated dynamic model of typhoid transmission was used to project health outcomes over a 30-year analytical horison for each scenario. Cost-of-illness data were drawn from the Surveillance of Typhoid Fever in Indonesia study and published literature. Incremental cost-effectiveness ratios (ICERs) were estimated from healthcare sector and societal perspectives. Uncertainty was explored using one-way sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA). Budget impact analysis supported annual fiscal planning. Six-year budget impact costs were US$61 million (routine) and US$251 million (routine and catch-up), equivalent to 0.48%-2.95% and 2.97%-9.84% of the annual national immunisation budget, respectively. Compared to no vaccination, routine TCV yielded ICERs at US$240.6 and US$238.8 per DALY averted from the healthcare sector and societal perspectives, respectively, corresponding to 5% of GDP per capita. Compared with routine immunisation alone, adding a catch-up campaign yielded ICERs of US$521.3 and US$519.5 per DALY averted from the healthcare sector and societal perspective, respectively, corresponding to approximately 11% of GDP per capita. OWSA showed that both strategies remained very cost-effective at a willingness-to-pay threshold of 1xGDP. PSA estimated probabilities of cost-effectiveness of 99.7% (routine and catch-up vs. routine) and 99.2% (routine vs. no vaccination). The multi-strategy cost-effectiveness acceptability curve identified the combined routine and catch-up campaign as the optimal strategy. Introducing TCV into Indonesia's NIP is projected to be very cost-effective. A routine-only program requires a lower budget, but adding a catch-up campaign is an optimal strategy with greater public health impact while remaining very cost-effective. Gates Foundation grants to Murdoch Children's Research Institute in collaboration with Universitas Gadjah Mada [ref. no. INV-003867] and to TyVAC 2.0 [ref. no. INV-030857].
proteins
2026-04-13 | Typhoid Toxin of Salmonella enterica Induces ISG15 Responses Mediating Host Cell Survival and Counteracting Intracellular Infection.
The typhoid toxin is a secreted virulence factor of typhoidal serovars of the bacterial pathogen Salmonella enterica implicated in typhoid fever and chronic infections. The toxin causes a DNA damage response in human cells, characterised by cell-cycle arrest and cellular distension, resulting in cellular senescence and increased bacterial burden. To better understand host responses to typhoid toxin, we performed a transcriptomic analysis of intoxicated host cells and found that the toxin induced expression of genes relating to the type-I interferon response, including the ubiquitin-like protein ISG15. ISG15 was upregulated in a STING-dependent manner, reduced bacterial burden, and was found to be critical to host cell survival in response to the typhoid toxin and interferon. This highlights ISG15 as an important component of the host cell defence to the typhoid toxin.
2026-01-16 | A new mouse model of typhoid fever using Salmonella enterica serovar Paratyphi C as a surrogate pathogen.
Salmonella enterica serovar (S.) Typhi, the etiological agent of typhoid fever, is strictly human adapted, which presents a significant challenge for studying its pathogenesis in animal models. A common strategy to overcome this limitation is to infect mice with S. Typhimurium as a surrogate pathogen. Since S. Typhimurium is a non-typhoidal serovar that does not encode the virulence-associated capsular polysaccharide (Vi antigen) of S. Typhi, we explored whether the mouse virulent typhoidal Salmonella serovar Paratyphi C, which expresses the Vi antigen, would be better suited as a surrogate pathogen to study typhoid fever pathogenesis in the mouse. In contrast to the nontyphoidal serovar Typhimurium, which produced lethal morbidity in C57BL/6 mice within a few days after infection, S. Paratyphi C demonstrated prolonged colonization of systemic organs for up to 28 days after infection. Analysis of virulence factors revealed that the Vi antigen was important at very early stages after infection (up to 2 days), whereas the type III secretion system encoded by Salmonella pathogenicity island 2 became critical at later stages. Vaccination with purified Vi antigen suppressed S. Paratyphi C dissemination. Implantation of a biotelemetry device revealed that S. Paratyphi C triggered fever after an incubation period of 3 days, which was reminiscent of the prolonged incubation period of typhoid fever. In conclusion, our findings suggest that the use of S. Paratyphi C as a surrogate pathogen provides a mouse model for studying typhoid fever pathogenesis and vaccine development.IMPORTANCEThe emergence of extensively drug-resistant Salmonella enterica serovar (S.) Typhi poses a serious threat to public health, but its host restriction to humans poses a challenge for studying pathogenesis and vaccine development in animal models. Here, we used S. Paratyphi C, a mouse virulent typhoidal serovar that expresses the virulence-associated Vi capsular polysaccharide, as a surrogate pathogen for studying typhoid fever in a mouse model. Our model recapitulates key features of typhoid fever, including clinical symptoms such as a prolonged incubation period, fever, and splenomegaly. Notably, disseminated infection with S. Paratyphi C developed after inoculation by the natural oral route. We demonstrate the utility of this model for studying pathogenesis and vaccination. We conclude that our new mouse model for typhoid fever offers a promising platform for evaluating novel therapeutics and vaccine candidates to address the problem of drug resistance in S. Typhi and reduce the global burden of typhoid fever.
2025-10-29 | Lacticaseibacillus rhamnosus D1 Fermented Milk Confers Protection Against Typhoid Fever Through Immunomodulation and Gut Microbiota Regulation in Mice.
This study investigated the protective effect of fermented milk by Lacticaseibacillus rhamnosus D1 in a murine model of Typhoid fever, focusing on cytokines, antimicrobial peptides and microbiota modulation. BALB/c mice were pre-treated with milk fermented by L. rhamnosus D1 prior to Salmonella Typhimurium challenge. Outcomes assessed included survival, weight change, bacterial translocation, mRNA expression of cytokines and antimicrobial peptides, in addition to gut microbiota modulation. Mice receiving fermented milk exhibited higher survival rates, reduced bacterial translocation and attenuated weight loss compared to controls. mRNA expression analyses revealed that L. rhamnosus D1 pre-treatment suppressed the expression of pro-inflammatory cytokines (IFN-γ, IL-6 and IL-12) and upregulated anti-inflammatory cytokines (IL-5, IL-10 and TGF-β), as well as antimicrobial peptides (Reg3β, Reg3γ and Lcn2). Furthermore, we observed that the consumption of fermented milk changed the gut microbiota of infected mice, not only by modulating the existing taxa, but also by facilitating the emergence of unique, potentially beneficial microbial lineages, such as Muribaculum, Roseburia, Intestinimonas, Bdellovibrio and Facklamia. These findings indicate that L. rhamnosus D1 protected mice against S. Typhimurium infection through immunomodulatory and microbiota-mediated mechanisms, changing mucosal immunity and strengthening the intestinal barrier by modulating gut microbiota and immune responses, in addition to promoting host antimicrobial defenses.
2025-09-22 | FliC adjuvant augments protective efficacy of recombinant T2544 antigen against SalmonellaTyphiand Paratyphi A by increasing serum antibodies, intestinal secretory immunoglobulin A and T cell memory.
The need for safe, effective, and affordable vaccines against Salmonella Typhi and Paratyphi A remains urgent, particularly in endemic regions of Asia and Africa. Contrary to earlier beliefs, parenteral vaccines can induce mucosal immunity, especially when combined with mucosal trafficking signals. Recent findings show that systemic delivery of soluble flagellin (FliC) activates CD103+ dendritic cells via TLR5, promoting mucosal IgA and regulatory T cell responses. Building on this, we evaluated recombinant FliC (rFliC) from S. Typhimurium as an adjuvant to enhance both systemic and mucosal immunity of rT2544, a subunit vaccine candidate. Female BALB/c mice were immunized subcutaneously with varying doses of rT2544 and rFliC to identify an optimal formulation. The selected dose (5 μg rT2544 + 2.5 μg rFliC) was tested for humoral and cellular responses, including serum IgG/IgA titers, antibody-secreting cells, cytokines (IFN-γ, IL-4, IL-17), and CTL activity. Protective efficacy was evaluated in an iron-overload mouse model challenged with S. Typhiand S. Paratyphi A, by assessing survival and bacterial loads in the intestine, liver, and spleen. Co-administration of rFliC with rT2544 enhanced systemic IgG and intestinal IgA responses, with increased ASCs and strong bactericidal activity against S. Typhiand S. Paratyphi A. The vaccine induced robust Th1, Th2, and Th17 cytokines, and improved CTL activity. Immunized mice showed 83 % and 91 % survival against S. Typhiand S. Paratyphi A, respectively, with significantly reduced bacterial loads in the intestine, liver, and spleen. Importantly, subcutaneous rFliC delivery effectively induced intestinal sIgA, eliminating the need for mucosal administration. Subcutaneous co-administration of rFliC induced strong antigen-specific mucosal sIgA, overcoming limitations of conventional mucosal adjuvants. The rFliC-adjuvanted rT2544 elicited robust humoral, mucosal, and cellular responses, providing significant protection against S. Typhiand S. Paratyphi A. These findings support its potential as a promising injectable subunit vaccine for enteric fever.
2025-07-23 | Salmonella Typhi gut invasion drives hypoxic immune subsets associated with disease outcomes.
Salmonella Typhi (S. Typhi), the causative agent of typhoid disease, remains a major public health concern. Owing to the human-restricted nature of S. Typhi, studies of typhoid pathogenesis in animal models are limited to a murine non-typhoidal pathogen. More recently, human challenge models have been conducted, providing insight into immune correlates of infection outcomes, which are still incompletely understood. Here, we performed an integrated single-cell analysis of immune responses from the human S. Typhi challenge model and mouse model of typhoid disease, to associate biological mechanism with human infection outcome. Most prominent, we revealed immune subsets with a hypoxia-related signature in the blood of individuals who developed disease in the human challenge model. This signature was also evident in the mouse model in activated macrophages infiltrating into the Peyer's patches, but not during infection with a mutant strain impaired for gut invasion. We further identified hypoxia-related signature as a general immune correlate of disease outcome in other infection-and inflammatory-related diseases. Collectively, we identified a hypoxia-associated immune signature that correlates with disease outcomes in humans. Using a mouse model, we demonstrated that this signature is driven by bacterial invasion to the Peyer's patches, implicating a causal role in the pathogenesis of typhoid fever.
other
2026-09-23 | Impaired acid stress resistance in Salmonella Typhi Ty2.
Salmonella enterica encounters acid stress during gastrointestinal transit and within the phagosomal environment of macrophages. Acid stress resistance has been well characterized in Salmonella enterica serovar Typhimurium, but comparative studies in the human-adapted Salmonella enterica serovar Typhi are limited. We compared the growth of S. Typhimurium 14028s and S. Typhi Ty2 at pH values ranging from 3 to 8 and observed that Salmonella enterica serovar Typhimurium exhibits enhanced growth at pH 4.5 compared to S. Typhi. Comparative transcriptomic profiling of S. Typhimurium and S. Typhi at pH 4.5 and 7.5 identified numerous differentially expressed acid-induced genes (DEGs), including genes encoding membrane proteins (OmpC, PhoE, HydB), a transcriptional regulator (RpoS), and stress response proteins (YciG, STM14_1829, YmdF). Targeted deletion of selected genes in S. Typhimurium significantly suppressed growth at acidic pH, confirming their role in acid stress resistance. These resistance mechanisms are compromised in S. Typhi due to pseudogenization. Heterologous expression of pseudogenized genes in S. Typhi restored acid tolerance. Collectively, these findings suggest that S. Typhi has lost the ability to withstand acid stress due to genomic decay and the loss of multiple genes essential for acid survival in S. Typhimurium, reflecting divergent evolutionary paths in these two serovars. Salmonella Typhimurium must adapt to acidic pH conditions in the intestinal tract and the intracellular environment to cause infection. In this study, we show that the enteric fever serovar Salmonella Typhi exhibits impaired growth at pH 4.5 in comparison to Salmonella Typhimurium. We further show that the loss of specific membrane proteins, a transcriptional regulator, and a family of stress response proteins in Salmonella Typhi are responsible for this difference. Collectively, these observations suggest that Salmonella Typhi has evolutionarily lost the ability to withstand acid stress due to differences in its interaction with the human host. This has important implications for the pathogenesis of typhoid fever.
2026-05-04 | Advancing Needle-Free Jet Injectors for Global Vaccine Delivery.
Background: Global immunization programs continue to rely on needle-based injections despite persistent concerns regarding sharps disposal, accidental injuries, and the technical skill required for accurate intradermal administration. Needle-free jet injectors (NFJIs) are an alternative delivery method in which narrow, high-velocity liquid jets penetrate the skin without a needle. Contemporary designs, ranging from single-use disposable-syringe injectors to digitally controlled electromechanical devices, address historical safety issues and meet current WHO and FDA device expectations. Methods: Evidence from engineering analyses, preclinical modeling, and clinical trials was reviewed to characterize how jet velocity, nozzle structure, and formulation rheology influence skin penetration and drug dispersion. Published vaccine studies were examined for antibody responses, seroconversion, and reactogenicity compared with needle-syringe injection. Field vaccination campaign data from national campaigns and operational reports were evaluated to describe implementation steps, acceptability, and implementation constraints. Results: Published studies evaluating vaccines, including inactivated influenza, hepatitis B, typhoid, rabies, and measles, report antibody titers and seroconversion rates after NFJI administration that are comparable to those achieved with conventional intramuscular or intradermal needle injection. Needle-free delivery was associated with operational advantages in several immunization programs, including reduced sharps waste and improved vaccination rate during high-volume immunization campaigns. Local and systemic reactogenicity follows expected patterns, with slightly higher injection-site responses in some NFJI studies. Imaging and mechanical data confirm that jet performance depends on nozzle geometry and controlled pressure pulses. At the same time, formulation stability remains a critical determinant of successful jet-based vaccine administration, particularly for protein antigens, adjuvanted formulations, and emerging mRNA vaccines that may experience transient shear stress during high-velocity injection. Evidence from vaccination campaigns further indicates that needle-free jet injectors reduce sharps waste, simplify vaccine handling and administration procedures, and support rapid vaccine delivery in large-scale immunization programs. Conclusions: Needle-free jet injectors are a practical alternative to traditional needle-based injections for some vaccines. Their main benefits include enabling intradermal dose-sparing strategies, reducing reliance on sharps disposal methods, and enabling the efficient vaccination of large groups without compromising immunogenicity. Future research should define the physicochemical stability limits of biologic formulations subjected to jet injection and evaluate digitally controlled injectors capable of precise pressure modulation and adjustable delivery parameters. In addition, needle-free jet injection eliminates needle penetration and sharps handling, which may reduce needle-associated anxiety and improve vaccine acceptability among individuals with needle aversion.
2024-09-07 | Oral Treatment with Saccharomyces cerevisiae CNCM I-3856 Mitigates the Inflammatory Response Experimentally Induced by Salmonella enterica subsp. enterica Serovar Typhimurium in Mice.
Salmonella spp. are intracellular, Gram-negative pathogens responsible for a range of diarrheal diseases, which can present either as self-limited (gastroenteritis) or as a systemic form (typhoid fever), characterizing a serious public health problem. In this study, we investigated the therapeutic effects of oral administration of Saccharomyces cerevisiae CNCM I-3856 in a murine model infected with Salmonella Typhimurium (ST). This yeast species has previously demonstrated the potential to support immune function and reduce inflammation and the ability to exert antimicrobial activity, which is important considering the increasing prevalence of antibiotic-resistant bacteria. Our findings revealed that mice infected with ST and only treated with sterile saline exhibited a higher mortality rate and body weight loss. In contrast, mice treated with I-3856 showed a notable reduction in these adverse outcomes. The yeast demonstrated a high capacity for co-aggregation with the pathogen. Furthermore, the significant amounts of yeast found in the feces of treated mice suggest that intestinal colonization was effective, which was associated with several beneficial effects, including reduced intestinal permeability, which likely limits bacterial translocation to extraintestinal organs. Additionally, the administration of I-3856 reduced levels of sIgA and resulted in a decrease in the recruitment of neutrophils and eosinophils to infection sites, indicating a modulation of the inflammatory response. Histological analyses showed attenuated liver and intestinal lesions in the yeast-treated mice, corroborating the protective effects of the yeast. In conclusion, the results suggest that S. cerevisiae CNCM I-3856 has the potential to control the inflammatory response experimentally induced by S. Typhimurium when administered to mice.
2023-11-29 | Deletion of Salmonella enterica serovar Typhi tolC reduces bacterial adhesion and invasion toward host cells.
S. Typhi is a Gram-negative bacterium that causes typhoid fever in humans. Its virulence depends on the TolC outer membrane pump, which expels toxic compounds and antibiotics. However, the role of TolC in the host cell adhesion and invasion by S. Typhi is unclear. We aimed to investigate how deleting the tolC affects the adhesion and invasion of HT-29 epithelial and THP-1 macrophage cells by S. Typhi in vitro. We compared the adhesion and invasion rates of the wild-type and the tolC mutant strains of S. Typhi using in vitro adhesion and invasion assays. We also measured the expression levels of SPI-1 genes (invF, sipA, sipC, and sipD) using quantitative PCR. We found that the tolC mutant showed a significant reduction in adhesion and invasion compared to the wild-type strain in both cell types. We also observed that the expression of SPI-1 genes was downregulated in the tolC mutant. Our results suggest that TolC modulates the expression of SPI-1 genes and facilitates the adhesion and invasion of host cells by S. Typhi. Our study provides new insights into the molecular mechanisms of S. Typhi pathogenesis and antibiotic resistance. However, our study is limited by the use of in vitro models and does not reflect the complex interactions between S. Typhi and host cells in vivo.
2023-01-11 | Identification of collaborative cross mouse strains permissive to Salmonella enterica serovar Typhi infection.
Salmonella enterica serovar Typhi is the causative agent of typhoid fever restricted to humans and does not replicate in commonly used inbred mice. Genetic variation in humans is far greater and more complex than that in a single inbred strain of mice. The Collaborative Cross (CC) is a large panel of recombinant inbred strains which has a wider range of genetic diversity than laboratory inbred mouse strains. We found that the CC003/Unc and CC053/Unc strains are permissive to intraperitoneal but not oral route of S. Typhi infection and show histopathological changes characteristic of human typhoid. These CC strains are immunocompetent, and immunization induces antigen-specific responses that can kill S. Typhi in vitro and control S. Typhi in vivo. Our results indicate that CC003/Unc and CC053/Unc strains can help identify the genetic basis for typhoid susceptibility, S. Typhi virulence mechanism(s) in vivo, and serve as a preclinical mammalian model system to identify effective vaccines and therapeutics strategies.
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