Typhi Infection Research Articles

Locally acquired typhoid fever outbreak linked to chronic carriage in Ottawa, Canada, 2018-2022.

In Canada, Salmonella enterica serovar Typhi infections are uncommon and typically travel-related. In November 2021, Ottawa Public Health identified a link between two typhoid fever cases, with no recent history of international travel, to the same grocery store ready-to-eat counter. This report describes the outbreak response to a rare occurrence of chronic S. Typhi carriage in Ottawa, Ontario, Canada and provides recommendations for investigations of small-scale protracted outbreaks. We administered exposure questionnaires using a single interviewer approach, tested stool samples of contacts and food handlers, inspected food premises, collected food samples and reviewed takeout receipts. Social network, spatial and whole genome sequencing analyses were used to investigate additional possible links between cases. Seven people with typhoid fever and onset from October 2018 to May 2022 were linked to an asymptomatic chronic S. Typhi carrier. Whole-genome sequencing confirmed that all eight isolates matched the outbreak cluster. All cases and carrier resided within an eight km radius in Ottawa. The chronic carrier worked as a food handler at various locations of a grocery store chain, including the implicated ready-to-eat counter. Transmission occurred via food handling, shared workspaces and social and household networks. The chronic carrier was excluded from food handling until successful completion of treatment and clearance testing. We overcame the challenges of a small but prolonged outbreak by identifying an asymptomatic carrier using a multi-method approach including whole genome sequencing and social network analysis.

Prevalence of Salmonella Typhi, its associated factors and antimicrobial susceptibility profile among patients attending Hawassa University Comprehensive Specialized Hospital, Hawassa, Ethiopia

IntroductionSalmonella Typhi infections cause significant morbidity and mortality worldwide, especially in developing countries including Ethiopia. This study aimed to determine the prevalence of Salmonella Typhi, its associated factors and antibiotic susceptibility profile among suspected typhoid patients.MethodsA cross-sectional study was conducted on 270 typhoid fever suspected patients at Hawassa University Comprehensive Specialized Hospital from June 2022 to September 2022. Data were collected using questionnaires by face-to-face interview. Stool samples for microbiological culture, blood samples for S. Typhi IgM/Entero-check WB rapid test and isolates for antimicrobial susceptibility tests were used through standard procedures and according to the reagents manufactures’ instructions. Hygiene implementation of patients was also assessed using interview. Sociodemographic and clinical characteristics of the patient’s were considered. Descriptive statistics were used to summarize the data, and logistic regression model analysis was performed to assess associations between S. Typhi infection and the associated sociodemographic and clinical factors.ResultsThe prevalence of S. Typhi IgM/Entero-check WB rapid test and stool culture results were 3.3%; (95% CI: 1.5–5.6) and 3.7%; (95% CI: 1.9–6.3) respectively. Not washing hands after latrine [AOR = 0.85, 95% CI (0.15–4.79), p = 0.05] is not significant but, not washing hands before meal [AOR = 0.053, 95% CI (0.08–0.36), p = 0.03], eating raw vegetables [AOR = 0.024, 95% CI (0.001–0.48), p = 0.015] and drinking water from a stream [AOR = 0.12, 95% CI (0.19–0.70), p = 0.001] were significantly associated with S. Typhi infection, but in terms of AOR, all are preventive. Susceptibility of isolates was 9/10 (90%), 8/10 (80%), and 8/10 (80%) to ciprofloxacin, ceftriaxone, and chloramphenicol, respectively. The majorities 100% and 80% of the isolates were resistant to ampicillin and cotrimoxazole, respectively. About 40% of the isolates were MDR.ConclusionThe prevalence of Salmonella Typhi with MDR has been observed. Therefore, health programmers and stakeholders should make efforts to improve the habit of sanitation, strengthen the capacity of laboratory diagnostic methods and increase awareness of the misprescription and misuse of antibiotics to reduce the impact of MDR bacteria.

Multidrug-resistant Salmonella Typhi among symptomatic and asymptomatic children in informal settlements in Nairobi, Kenya

BackgroundThe emergence and persistence of multidrug-resistant (MDR) Salmonella Typhi (S. Typhi) infections is a significant global health problem. The carrier state of typhoid makes it prudent to conduct routine surveillance for both acute cases and carriers especially those caused by MDR S. Typhi. We report on the prevalence of MDR S. Typhi, resistance phenotypes and antimicrobial resistance genes detected in symptomatic and asymptomatic children living in informal settlements in Nairobi, Kenya.Methods215 archived presumed S. Typhi isolates from stool samples provided by children ≤ 16 years collected from 2013 to 2018 were revived in May, 2022 and confirmed using culture and antisera serotyping. The Kirby Bauer disc diffusion technique was used to test the S. Typhi against 14 antibiotics. The MDR S. Typhi (resistant to ampicillin, chloramphenicol and sulfamethoxazole trimethoprim) which in addition were also resistant to either a cephalosporin or a fluoroquinolone were analyzed for Beta lactams and quinolone resistance genes using polymerase chain reaction.ResultsA total of 215 isolates were confirmed to be positively S. Typhi; of these, 105 (49%) and 110 (51%) were from symptomatic and asymptomatic children respectively. On average, S. Typhi resistance from asymptomatic and symptomatic children against 1st line drugs was observed at; 77% &70%, ampicillin; 60% & 64%, sulfamethoxazole-trimethoprim, and 45% & 54%, chloramphenicol respectively. Multi drug resistance was observed in 90 (42%) of the isolates, of these, 44 (49%) were isolated from symptomatic and 46 (51%) from asymptomatic children. Fifteen resistance phenotypes (p) were observed with, ampicillin/chloramphenicol/sulfamethoxazole-trimethoprim/nalidixic acid (amp/chl/sxt/na) as the most common among the symptomatic 43/90 (48%) and asymptomatic 55/90 (61%) children. The blaTEM−D, AMR genes were detected in 37/44 (84%) S. Typhi isolates, out of this 18 (49%) were from symptomatic while 19 (51%) were from asymptomatic children respectively.ConclusionThe carriage of MDR S. Typhi among the asymptomatic children is concerning as they can act as potential transmitters of the typhoid disease to unsuspecting children. These study findings highlight the need for continued surveillance of antimicrobial resistance and mass immunization of children living in these urban informal areas.

Role of circulating T follicular helper subsets following Ty21a immunization and oral challenge with wild type S. Typhi in humans.

Despite decades of intense research, our understanding of the correlates of protection against Salmonella Typhi (S. Typhi) infection and disease remains incomplete. T follicular helper cells (TFH), an important link between cellular and humoral immunity, play an important role in the development and production of high affinity antibodies. While traditional TFH cells reside in germinal centers, circulating TFH (cTFH) (a memory subset of TFH) are present in blood. We used specimens from a typhoid controlled human infection model whereby participants were immunized with Ty21a live attenuated S. Typhi vaccine and then challenged with virulent S. Typhi. Some participants developed typhoid disease (TD) and some did not (NoTD), which allowed us to assess the association of cTFH subsets in the development and prevention of typhoid disease. Of note, the frequencies of cTFH were higher in NoTD than in TD participants, particularly 7 days after challenge. Furthermore, the frequencies of cTFH2 and cTFH17, but not cTFH1 subsets were higher in NoTD than TD participants. However, we observed that ex-vivo expression of activation and homing markers were higher in TD than in NoTD participants, particularly after challenge. Moreover, cTFH subsets produced higher levels of S. Typhi-specific responses (cytokines/chemokines) in both the immunization and challenge phases. Interestingly, unsupervised analysis revealed unique clusters with distinct signatures for each cTFH subset that may play a role in either the development or prevention of typhoid disease. Importantly, we observed associations between frequencies of defined cTFH subsets and anti-S. Typhi antibodies. Taken together, our results suggest that circulating TFH2 and TFH17 subsets might play an important role in the development or prevention of typhoid disease. The contribution of these clusters was found to be distinct in the immunization and/or challenge phases. These results have important implications for vaccines aimed at inducing long-lived protective T cell and antibody responses.

The use of controlled human infection models to identify correlates of protection for invasive Salmonella vaccines.

Controlled human infection model (CHIM) studies, which involve deliberate exposure of healthy human volunteers to an infectious agent, are recognised as important tools to advance vaccine development. These studies not only facilitate estimates of vaccine efficacy, but also offer an experimental approach to study disease pathogenesis and profile vaccine immunogenicity in a controlled environment, allowing correlation with clinical outcomes. Consequently, the data from CHIMs can be used to identify immunological correlates of protection (CoP), which can help accelerate vaccine development. In the case of invasive Salmonella infections, vaccination offers a potential instrument to prevent disease. Invasive Salmonella disease, caused by the enteric fever pathogens Salmonella enterica serovar Typhi (S. Typhi) and S. Paratyphi A, B and C, and nontyphoidal Salmonella (iNTS), remains a significant cause of mortality and morbidity in low- and middle-income countries, resulting in over 200,000 deaths and the loss of 15 million DALYs annually. CHIM studies have contributed to the understanding of S. Typhi infection and provided invaluable insight into the development of vaccines and CoP following vaccination against S. Typhi. However, CoP are less well understood for S. Paratyphi A and iNTS. This brief review focuses on the contribution of vaccine-CHIM trials to our understanding of the immune mechanisms associated with protection following vaccines against invasive Salmonella pathogens, particularly in relation to CoP.

Exploring the Antimicrobial Resistance Profile of Salmonella typhi and Its Clinical Burden.

Background: Typhoid fever caused by Salmonella enterica serovar Typhi (S. typhi) continues to pose a significant risk to public health in developing countries, including Pakistan. This study investigated the epidemiological factors linked to suspected and confirmed S. typhi infections in Peshawar's hospital population. Methodology: A total of 5735 blood samples of patients with suspected enteric fever were collected from September 2022 to November 2023. S. typhi infection was confirmed using microbiological culture of blood samples, biochemical-based tests, and DNA-sequencing methods. Drug sensitivity testing on cultures was conducted as per the CLSI guidelines. Chi-square tests were used to analyze the clinical and epidemiologic characteristics of 5735 samples stratified by S. typhi infection status, and risk factors were assessed by applying logistic regression models to estimate odds ratios (ORs). Results: The number of confirmed typhoid fever cases in this hospital-based study population was 691 (/5735, 12.0%), more prevalent in males (447/3235 13.8%) and children (0-11 years) (429/2747, 15.6%). Compared to children, the risk of S. typhi infection was lower in adolescence (adjusted OR = 0.52; 95% CI: 0.42-0.66), adulthood (19-59 years; aOR = 0.30; 95% CI: 0.25-0.38), and older adulthood (aOR = 0.08; 95% CI: 0.04-0.18) (p < 0.001). Compared to males, the risk of S. typhi infection was lower in females (aOR = 0.67; 95% CI = 0.56-0.80; p = 0.002). Living in a rural residence (compared to urban) was associated with a higher risk of infection (aOR = 1.38; 95% CI: 1.16-1.63; p = 0.001), while access to a groundwater source (compared to municipal water supply) led to a lower risk (aOR = 0.56; 95% CI: 0.43-0.73; p = 0.002). Vaccination demonstrated a robust protective effect (aOR = 0.069; 95% CI = 0.04-0.11, p = 0.002). For those with typhoid infections, clinical biomarker analysis revealed the presence of leucopenia (65/691, 9.4%), thrombocytopenia (130/691, 18.8%), and elevated alanine aminotransferase (ALT) (402/691, 58.2%) and C-reactive protein (CRP) (690/691, 99.9%) levels. Worryingly, among the positive S. typhi isolates, there was a high prevalence of drug resistance (653/691), including multidrug-resistant (MDR 82/691, 11.9%) and extensively drug-resistant types (XDR, 571/691, 82.6%). Conclusions: This study highlights the importance of age, sex, locality, water source, and vaccination status in shaping the epidemiological landscape of S. typhi in the Peshawar district. It implies that expanding vaccination coverage to the broader population of Khyber Pakhtunkhwa province, particularly in the district of Peshawar, would be beneficial.

Exploring the antimicrobial efficacy of Manuka honey against multidrug-resistant and extensively drug-resistant Salmonella Typhi causing septicemia in Pakistan.

Aim: To determine the efficacy of manuka honey against multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical strains of Salmonella Typhi.Materials & methods: Clinical isolates were processed using the Bactec blood culture system, identificationand antibiogram by Vitek 2and antibiotic resistance genes through polymerase chain reaction (PCR). Microbroth dilution assays evaluated the antibacterial activity of manuka honey.Results: MDR and XDR-S. Typhi was susceptible to azithromycin. These strains carried the H58, gyrA, gyrB, blaCTX-M-15, and blaTEM-1 genes. At 100% honey, the zone of inhibition for MDR (15-23mm) and XDR (15-24mm) strains. 18/50 MDR and 14/50 XDR strains inhibited at 3.125v/v% killed at 6.25v/v% concentration respectively.Conclusion: Manuka honey could be an alternative option for treating S. Typhi infections.

Extended Drug Resistant Typhoid Fever; A Case Report

Enteric fever is a potentially fatal multisystem illness caused primarily by Salmonella typhi and, to a lesser extent, by Para typhi A, B, and C. Decades of indiscriminate usage of Antibiotics has led to emergence of multiple resistant strains. Multi drug resistant strains against Salmonella typhi has made treatment options limited and costly. According to WHO an estimated 11–20 million people get sick from typhoid all over the world. In the year 2022 an outbreak of Enteric fever emerged in April and spread all over Pakistan. This created a great concern as the causative organism were mostly Multi drug resistant. We recently have documented a case of extended drug resistant (XDR) Enteric Fever with a complicated clinical course, responding only to Carbapenem (Meropenem/Imipenem). The purpose of reporting this case was to highlight the morbidity, cost and therapeutic challenges which are associated with severe XDR S. typhi infection in Pakistan

Extended Drug Resistant Typhoid Fever; A Case Report

Enteric fever is a potentially fatal multisystem illness caused primarily by Salmonella typhi and, to a lesser extent, by Para typhi A, B, and C. Decades of indiscriminate usage of Antibiotics has led to emergence of multiple resistant strains. Multi drug resistant strains against Salmonella typhi has made treatment options limited and costly. According to WHO an estimated 11–20 million people get sick from typhoid all over the world. In the year 2022 an outbreak of Enteric fever emerged in April and spread all over Pakistan. This created a great concern as the causative organism were mostly Multi drug resistant. We recently have documented a case of extended drug resistant (XDR) Enteric Fever with a complicated clinical course, responding only to Carbapenem (Meropenem/Imipenem). The purpose of reporting this case was to highlight the morbidity, cost and therapeutic challenges which are associated with severe XDR S. typhi infection in Pakistan

Extended Drug Resistant Typhoid Fever; A Case Report

Enteric fever is a potentially fatal multisystem illness caused primarily by Salmonella typhi and, to a lesser extent, by Para typhi A, B, and C. Decades of indiscriminate usage of Antibiotics has led to emergence of multiple resistant strains. Multi drug resistant strains against Salmonella typhi has made treatment options limited and costly. According to WHO an estimated 11–20 million people get sick from typhoid all over the world. In the year 2022 an outbreak of Enteric fever emerged in April and spread all over Pakistan. This created a great concern as the causative organism were mostly Multi drug resistant. We recently have documented a case of extended drug resistant (XDR) Enteric Fever with a complicated clinical course, responding only to Carbapenem (Meropenem/Imipenem). The purpose of reporting this case was to highlight the morbidity, cost and therapeutic challenges which are associated with severe XDR S. typhi infection in Pakistan

Flea-Borne Rickettsioses and Scrub Typhus in Patients with Suspected Arbovirus Infection in Bangkok, Thailand.

Background: In urban Thailand, arboviral infections dominate diagnoses of acute undifferentiated fevers (AUFs) owing to their well-defined epidemiology and characteristic clinical presentations. However, rickettsial diseases, also endemic in this setting, remain under-recognized owing to challenges in early detection. Objective: This study aimed to identify potential rickettsial infections among patients with AUF in Bangkok and vicinity utilizing leftover nucleic acid extracted from serum samples from patients initially suspected of but negative for arbovirus infections. Materials and Methods: A total of 609 nucleic acid samples were screened for rickettsial bacteria using real-time PCR, targeting the 17-kDa common antigen gene of Rickettsia spp. and the 47-kDa gene of Orientia tsutsugamushi. Results: Nine samples were positive for Rickettsia spp. and two were positive for O. tsutsugamushi. DNA sequence and phylogenetic analyses based on partial 17-kDa antigen and citrate synthase (gltA) genes identified the Rickettsia-positive samples as R. typhi in eight cases and R. felis in one case. Analysis of the 56-kDa type-specific antigen gene identified the two O. tsutsugamushi isolates as Gilliam-related genotypes. Although rickettsial diseases typically present with mild symptoms, two patients with R. typhi infection (murine typhus) developed respiratory distress syndrome, highlighting the potential for rare but serious complications. Conclusion: This study underscores the critical importance of differential diagnosis and prompt, effective intervention to prevent complications in suspected cases.

Synergistic Effect of Combination Antibiotics against Multidrug-Resistant Salmonella enterica serovar Typhi

Background: Infection caused by multidrug-resistant (MDR) Salmonella enterica serovar Typhi (S. Typhi) is a major health problem in low- and middle-income countries (LMICs). S. Typhi has been reported to be resistant to fluoroquinolones and cephalosporins. Objective: To find out the anti-microbial activity of combination antibiotics against resistant S. typhi. Materials and Methods: First, single antibiotic disks of ciprofloxacin, imipenem and vancomycin with the concentrations of 20, 40, 60 and 80 μg/ml were prepared and applied against sensitive S. typhi to confirm its susceptibility. Later, a resistant strain of Shigella flexneri was treated with single antibiotic (ciprofloxacin, vancomycin and imipenem) at the highest concentration (80 μg/ml) to determinets resistant behavior by measuring the zones of inhibition obtained from the disc diffusion assay. Co-culture was performed between the sensitive and resistant strains to develop the resistant strain of S. typhi. Combinations of antibiotics were used for susceptibility testing against the newly resistant strain of S. typhi by using Kirby–Bauer disk diffusion method. Experiments were carried out in triplicates and the average reading was recorded. Results: The study showed that different concentrations of the combination of vancomycin and imipenem (20, 40, 60, 80 μg/ml) exhibited 18, 20, 24- and 29-mm respective zone of inhibition (ZOI) against S. typhi. A combination of ciprofloxacin and imipenem also exhibited optimum ZOI. It was observed in this study that a single antibiotic treatment did not show any activity against newly resistant strains of S. typhi. Conclusions: The combination therapy can be used as a beneficial treatment approach in multi-drug resistant S. typhi infections. Dhaka Univ. J. Pharm. Sci. 23(1): 37-42, 2024 (June)

Transcriptional profiling links unique human macrophage phenotypes to the growth of intracellular Salmonella enterica serovar Typhi

Macrophages provide a crucial environment for Salmonella enterica serovar Typhi (S. Typhi) to multiply during typhoid fever, yet our understanding of how human macrophages and S. Typhi interact remains limited. In this study, we delve into the dynamics of S. Typhi replication within human macrophages and the resulting heterogeneous transcriptomic responses of macrophages during infection. Our study reveals key factors that influence macrophage diversity, uncovering distinct immune and metabolic pathways associated with different stages of S. Typhi intracellular replication in macrophages. Of note, we found that macrophages harboring replicating S. Typhi are skewed towards an M1 pro-inflammatory state, whereas macrophages containing non-replicating S. Typhi exhibit neither a distinct M1 pro-inflammatory nor M2 anti-inflammatory state. Additionally, macrophages with replicating S. Typhi were characterized by the increased expression of genes associated with STAT3 phosphorylation and the activation of the STAT3 transcription factor. Our results shed light on transcriptomic pathways involved in the susceptibility of human macrophages to intracellular S. Typhi replication, thereby providing crucial insight into host phenotypes that restrict and support S. Typhi infection.

Comparative Assessment of Antibacterial Activity of Commercially Available Antibiotics and Cinnamomum Verum (Cinnamon) Against Salmonella Typhi and Para Typhi Infections

Comparative Assessment of Antibacterial Activity of Commercially Available Antibiotics and Cinnamomum Verum (Cinnamon) Against Salmonella Typhi and Para Typhi Infections

Epidemiology of Murine Typhus in Taiwan from 2013 to 2020.

Murine typhus is a flea-borne disease caused by Rickettsia typhi infection. The disease is a notifiable infectious disease in Taiwan. Specimens from suspected cases are required to be sent to the Taiwan Centers for Disease Control and Prevention for laboratory diagnosis. In this study, 204 cases of murine typhus were identified by bacterial isolation, real-time polymerase chain reaction, or indirect immunofluorescence assay between 2013 and 2020. The average incidence rate was 0.11/100,000 person-years (95% CI: 0.08-0.13). Murine typhus occurred throughout the year, but it was most prevalent in summer (May to August). The majority of patients were males (75%), residents of Kaohsiung city (31%), and worked in agriculture, forestry, fishing, and animal husbandry (27%). Fever was the most common symptom, present in 95.6% of patients, followed by headache (41%), myalgia (33%), and liver dysfunction (33%). Only 13% of patients had a rash. Up to 80% of cases were among hospitalized patients, and 43% of patients developed severe manifestations. Serological assays also indicated coinfection events. Seven patients showed a 4-fold increase in antibody titers against Orientia tsutsugamushi (N = 2), Coxiella burnetii (n = 2), and Leptospira (N = 3). In conclusion, murine typhus is an endemic and important zoonotic rickettsial disease in Taiwan that cannot be ignored. Further epidemiological surveillance and clinical characteristics should be continuously investigated to prevent and control murine typhus.

Early host immune responses in a human organoid-derived gallbladder monolayer to Salmonella Typhi strains from patients with acute and chronic infections: a comparative analysis.

Salmonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen, invades the host through the gut to cause typhoid fever. Recent calculations of the typhoid fever burden estimated that more than 10 million new typhoid fever cases occur in low and middle-income countries, resulting in 65,400-187,700 deaths yearly. Interestingly, if not antibiotic-treated, upon the resolution of acute disease, 1%-5% of patients become asymptomatic chronic carriers. Chronically infected hosts are not only critical reservoirs of infection that transmit the disease to naive individuals but are also predisposed to developing gallbladder carcinoma. Nevertheless, the molecular mechanisms involved in the early interactions between gallbladder epithelial cells and S. Typhi remain largely unknown. Based on our previous studies showing that closely related S. Typhi strains elicit distinct innate immune responses, we hypothesized that host molecular pathways activated by S. Typhi strains derived from acutely and chronically infected patients would differ. To test this hypothesis, we used a novel human organoid-derived polarized gallbladder monolayer model, and S. Typhi strains derived from acutely and chronically infected patients. We found that S. Typhi strains derived from acutely and chronically infected patients differentially regulate host mitogen-activated protein kinase (MAPK) and S6 transcription factors. These variations might be attributed to differential cytokine signaling, predominantly via TNF-α and IL-6 production and appear to be influenced by the duration the isolate was subjected to selective pressures in the gallbladder. These findings represent a significant leap in understanding the complexities behind chronic S. Typhi infections in the gallbladder and may uncover potential intervention targets.

Antibiotic resistance pattern of &lt;em&gt;Salmonella enterica typh&lt;/em&gt;i infection in paediatric population at a iertiary level hospital

Background: Enteric fever is an important public health condition in developing countries. Antibiotic resistance patterns in Salmonella enterica typhi (S. typhi) infections are constantly changing. Continual surveillance of resistance levels of S. typhi is critical for clinicians to update antibiotic options.Objectives: To evaluate the current trends in antibiotic sensitivity and resistance to S. typhi in children in developing countries.Method: A cross sectional observational study was carried out on 102 children aged 6 months to 5 years with culture positive S. typhi infection in a tertiary care hospital in North India. Antibiotic susceptibility information of S. typhi was collected and the pattern of antibiotic resistance was analysed.Results: S. typhi showed a sensitivity of 78.4% to ampicillin and 99% to trimethoprim+ sulfamethoxazole which were the previously used antibiotics. However, it showed 100% resistance to ciprofloxacin and nalidixic acid. Of the currently used first line IV antibiotics, there was a 88.4% sensitivity to ceftriaxone and a 98% sensitivity to meropenem.Conclusions: The study concluded that there is reemergence of antibiotic sensitivity of S. typhi to earlier first line drugs like ampicillin and trimethoprim– sulfamethoxazole.

Estimating the subnational prevalence of antimicrobial resistant Salmonella enterica serovars Typhi and Paratyphi A infections in 75 endemic countries, 1990-2019: a modelling study.

Enteric fever, a systemic infection caused by Salmonella enterica serovars Typhi and Paratyphi A, remains a major cause of morbidity and mortality in low-income and middle-income countries. Enteric fever is preventable through the provision of clean water and adequate sanitation and can be successfully treated with antibiotics. However, high levels of antimicrobial resistance (AMR) compromise the effectiveness of treatment. We provide estimates of the prevalence of AMR S Typhi and S Paratyphi A in 75 endemic countries, including 30 locations without data. We used a Bayesian spatiotemporal modelling framework to estimate the percentage of multidrug resistance (MDR), fluoroquinolone non-susceptibility (FQNS), and third-generation cephalosporin resistance in S Typhi and S Paratyphi A infections for 1403 administrative level one districts in 75 endemic countries from 1990 to 2019. We incorporated data from a comprehensive systematic review, public health surveillance networks, and large multicountry studies on enteric fever. Estimates of the prevalence of AMR and the number of AMR infections (based on enteric fever incidence estimates by the Global Burden of Diseases study) were produced at the country, super-region, and total endemic area level for each year of the study. We collated data from 601 sources, comprising 184 225 isolates of S Typhi and S Paratyphi A, covering 45 countries over 30 years. We identified a decline of MDR S Typhi in south Asia and southeast Asia, whereas in sub-Saharan Africa, the overall prevalence increased from 6·0% (95% uncertainty interval 4·3-8·0) in 1990 to 72·7% (67·7-77·3) in 2019. Starting from low levels in 1990, the prevalence of FQNS S Typhi increased rapidly, reaching 95·2% (91·4-97·7) in south Asia in 2019. This corresponded to 2·5 million (1·5-3·8) MDR S Typhi infections and 7·4 million (4·7-11·3) FQNS S Typhi infections in endemic countries in 2019. The prevalence of third-generation cephalosporin-resistant S Typhi remained low across the whole endemic area over the study period, except for Pakistan where prevalence of third-generation cephalosporin resistance in S Typhi reached 61·0% (58·0-63·8) in 2019. For S Paratyphi A, we estimated low prevalence of MDR and third-generation cephalosporin resistance in all endemic countries, but a drastic increase of FQNS, which reached 95·0% (93·7-96·1; 3·5 million [2·2-5·6] infections) in 2019. This study provides a comprehensive and detailed analysis of the prevalence of MDR, FQNS, and third-generation cephalosporin resistance in S Typhi and S Paratyphi A infections in endemic countries, spanning the last 30 years. Our analysis highlights the increasing levels of AMR in this preventable infection and serves as a resource to guide urgently needed public health interventions, such as improvements in water, sanitation, and hygiene and typhoid fever vaccination campaigns. Fleming Fund, UK Department of Health and Social Care; Wellcome Trust; and Bill and Melinda Gates Foundation.

Systems and computational analysis of gene expression datasets reveals GRB-2 suppression as an acute immunomodulatory response against enteric infections in endemic settings.

Enteric infections are a major cause of under-5 (age) mortality in low/middle-income countries. Although vaccines against these infections have already been licensed, unwavering efforts are required to boost suboptimalefficacy and effectiveness in regions that are highly endemic to enteric pathogens. The role of baseline immunological profiles in influencing vaccine-induced immune responses is increasingly becoming clearer for several vaccines. Hence, for the development of advanced and region-specific enteric vaccines, insights into differences in immune responses to perturbations in endemic and non-endemic settings become crucial. For this reason, we employed a two-tiered system and computational pipeline (i) to study the variations in differentially expressed genes (DEGs) associated with immune responses to enteric infections in endemic and non-endemic study groups, and (ii) to derive features (genes) of importance that keenly distinguish between these two groups using unsupervised machine learning algorithms on an aggregated gene expression dataset. The derived genes were further curated using topological analysis of the constructed STRING networks. The findings from these two tiers are validated using multilayer perceptron classifier and were further explored using correlation and regression analysis for the retrieval of associated gene regulatory modules. Our analysis reveals aggressive suppression of GRB-2, an adaptor molecule integral for TCR signaling, as a primary immunomodulatory response against S. typhi infection in endemic settings. Moreover, using retrieved correlation modules and multivariant regression models, we found a positive association between regulators of activated T cells and mediators of Hedgehog signaling in the endemic population, which indicates the initiation of an effector (involving differentiation and homing) rather than an inductive response upon infection. On further exploration, we found STAT3 to be instrumental in designating T-cell functions upon early responses to enteric infections in endemic settings. Overall, through a systems and computational biology approach, we characterized distinct molecular players involved in immune responses to enteric infections in endemic settings in the process, contributing to the mounting evidence of endemicity being a major determiner of pathogen/vaccine-induced immune responses. The gained insights will have important implications in the design and development of region/endemicity-specific vaccines.

Protective effects of sodium humate and its zinc and selenium chelate on the oxidative stress, inflammatory, and intestinal barrier damage of Salmonella Typhimurium-challenged broiler chickens

The objective of this study was to investigate the protective effects and mechanisms of dietary administration of sodium humate (HNa) and its zinc and selenium chelate (Zn/Se-HNa) in mitigating Salmonella Typhimurium (S. Typhi) induced intestinal injury in broiler chickens. Following the gavage of 109 CFU S. Typhi to 240 broilers from 21-d to 23-d aged, various growth performance parameters such as body weight (BW), average daily gain (ADG), average daily feed intake (ADFI), and feed ratio (FCR) were measured before and after infection. Intestinal morphology was assessed to determine the villus height, crypt depth, and chorionic cryptologic ratio. To evaluate intestinal barrier integrity, levels of serum diamine oxidase (DAO), D-lactic acid, tight junction proteins, and the related genes were measured in each group of broilers. An analysis was conducted on inflammatory-related cytokines, oxidase activity, and Nuclear Factor Kappa B (NF-κB) and Nuclear factor erythroid2-related factor 2 (Nrf2) pathway-related proteins and mRNA expression. The results revealed a significant decrease in BW, ADG, and FCR in S. typhi-infected broilers. HNa tended to increase FCR (P = 0.056) while the supplementation of Zn/Se-HNa significantly restored BW and ADG (P < 0.05). HNa and Zn/Se-HNa exhibit favorable and comparable effects in enhancing the levels of serum DAO, D-lactate, and mRNA and protein expression of jejunum and ileal tight junction. In comparison to HNa, Zn/Se-HNa demonstrates a greater reduction in S. Typhi shedding in feces, as well as superior efficacy in enhancing the intestinal morphology, increasing serum catalase (CAT) activity, inhibiting pro-inflammatory cytokines, and suppressing the activation of the NF-κB pathway. Collectively, Zn/Se-HNa was a more effective treatment than HNa to alleviate adverse impact of S. Typhi infection in broiler chickens.