Typhoid Fever

Introduction

Typhoid fever, also known as enteric fever, is a significant global public health concern, causing an estimated 26.9 million new infections and 200,000 deaths annually.^[1]This systemic infection is primarily caused by the bacteriaSalmonella enterica serovar Typhi (S. Typhi) and, to a lesser extent, Salmonella enterica serovar Paratyphi (S. Paratyphi) pathovars A, B, or C.^[2] Transmission typically occurs through the consumption of food or water contaminated with fecal matter.^[2]While improvements in sanitation, industrialization, and access to clean water have effectively mitigated the disease burden in many developed nations, typhoid fever remains endemic in numerous lower-income countries.^[3]The outcome of an enteric fever infection is heavily influenced by the interaction between the human host and the pathogen.^[2] While the genetic diversity, virulence mechanisms, and epidemiology of S. Typhi have been studied extensively.^[4] understanding human genetic factors that determine susceptibility or resistance to enteric fever has been less clear.^[2] Recent genome-wide association studies (GWAS) have shed light on the host’s genetic contribution, identifying strong associations within the human leukocyte antigen (HLA) class II region. Specifically, a marker rs7765379 , located near the HLA-DQB1 and HLA-DRB1 genes, has been strongly associated with resistance to enteric fever.^[2] Further fine-mapping revealed that the classical HLA-DRB1*04:05 allele can explain this association, suggesting HLA-DRB1’s crucial role in resistance, likely through antigen presentation.^[2] This protective effect of HLA-DRB1*04:05represents one of the most substantial genetic effects observed for human susceptibility to an infectious disease, offering nearly a 5-fold greater resistance.^[2] Another SNP, rs6841458 , near GUCY1A3on chromosome 4, was also identified as associated with the disease.^[2] Clinically, individuals with enteric fever present with characteristic signs and symptoms, confirmed by culture of S. Typhi or S. Paratyphifrom blood or bone marrow.^[2] Although protective vaccines against S. Typhi exist, their efficacy is limited, and they are not suitable for young children, who are among the most vulnerable.^[2] Consequently, these vaccines are not widely adopted where they are most needed. A significant challenge also arises from the lack of a licensed vaccine against S. Paratyphi pathovars, which is particularly concerning given the increasing incidence of S. Paratyphi A infections in many parts of Asia.^[5] Research into HLA class II variation holds promise for informing the rational design of more effective vaccines against enteric fever and other invasive bacterial infections.^[2]

Methodological and Statistical Considerations

The study’s discovery stage, while a significant advance, was based on 432 individuals with culture-confirmed S. Typhiinfection and 2,011 controls, which might still limit the power to detect all genetic effects across the genome, particularly for variants with smaller effect sizes or lower minor allele frequencies.^[2] A key finding, the association with rs6841458 near GUCY1A3, did not replicate in the independent Nepalese cohort, suggesting that some initial associations may be specific to certain populations or represent false positives that require further validation.^[2] This highlights the inherent challenges in identifying robust genetic associations, especially when dealing with complex traits and diverse populations.

The statistical power calculations for the replication stages were designed to reliably detect modest genetic effects (odds ratio > 1.5–1.6) at minor allele frequencies exceeding 20%, and stronger effects (odds ratio > 3) even at lower frequencies.^[2]This implies that genetic variants with very subtle effects or those that are particularly rare within the studied populations might have been overlooked due to insufficient power, despite their potential contribution to typhoid fever resistance. Furthermore, the reliance on array-based genotyping and imputation, while robust, may not capture all types of genetic variation, such as structural variants or very rare coding mutations, which could also influence host susceptibility.

Population and Phenotypic Heterogeneity

The study cohorts were primarily drawn from specific populations in Vietnam (predominantly Vietnamese Kinh ancestry) and Nepal (a more diverse population with 15 self-reported ancestry groups), which restricts the generalizability of the findings to other global populations.^[2] Although principal component analysis and stratification by self-reported ancestry were employed to account for genetic stratification, the specific genetic architecture of host resistance to enteric fever could differ across various ethnic and geographical contexts. Additionally, the use of cord blood samples as population controls, while a common practice, introduces a potential age mismatch with the cases (children or adults), which could subtly influence the interpretation of genetic associations if age-related factors were not fully accounted for.

The definition of enteric fever cases was based on culture-confirmed S. Typhi or S. Paratyphi Ainfection, but the proportion of these pathogens varied significantly between the Vietnamese (>99%S. Typhi) and Nepalese (68% S. Typhi, 32% S. Paratyphi A) cohorts.^[2] While stratification by pathogen type did not significantly alter the association magnitude for rs7765379 , this heterogeneity suggests that the genetic basis for resistance might not be identical across different Salmonellaserovars. The study also focused on symptomatic clinical disease, potentially missing genetic factors that influence asymptomatic carriage or milder, undiagnosed infections, which are also crucial aspects of enteric fever epidemiology.

Unaccounted Genetic and Environmental Factors

The research identified a significant genetic association but did not comprehensively explore the complex interplay of environmental factors or gene-environment interactions, which are critical in determining the outcome of infectious diseases like typhoid fever.^[2]Environmental determinants such as sanitation, access to clean water, and nutritional status are known to profoundly impact disease incidence and severity, and these factors could modulate genetic susceptibility, yet they were not explicitly modeled in the genetic analyses. This omission means that the full spectrum of factors influencing typhoid fever resistance is likely broader than what was captured by the genetic data alone.

The study acknowledged a broader knowledge gap regarding “human host determinants influencing susceptibility to enteric fever,” noting that previous candidate gene studies were often limited by sample size.^[2] While this research advanced understanding by identifying HLA-DRB1 as a major contributor, the genetic effects explained represent only a fraction of the overall heritability, indicating that substantial “missing heritability” remains. This suggests that other genetic variants, including those in non-coding regions, structural variations, or epigenetic modifications, along with their interactions, contribute to the unexplained variation in host resistance. Further functional studies are also needed to fully elucidate the precise mechanisms by which the identified HLA-DRB1*04:05 allele confers resistance beyond its presumed role in antigen presentation.

Variants

The genetic landscape influencing an individual’s susceptibility to infectious diseases, such as typhoid fever, often involves complex interactions between host immune genes and environmental factors. Key variants in the Major Histocompatibility Complex (MHC) region, particularly near theHLA-DQB1 and HLA-DRB1 genes, have been identified as significant determinants of resistance to enteric fever. One such variant, *rs7765379 *, is located within this critical immune region, which is responsible for presenting pathogen-derived antigens to T-cells, thereby initiating adaptive immune responses. The minor allele of *rs7765379 *has been consistently observed to be under-represented in individuals diagnosed with enteric fever, indicating its role in conferring a protective effect against the disease.^[2] This protective association has been replicated in multiple independent cohorts, strengthening the evidence for its role in host defense against Salmonella Typhi and Salmonella Paratyphi infections.^[2] Further fine-mapping studies have revealed that the protective effect attributed to *rs7765379 * is largely explained by a specific classical HLA allele, HLA-DRB1*04:05, which exhibits strong linkage disequilibrium with *rs7765379 *. The HLA-DRB1*04:05 allele itself is a powerful protective factor, associated with an average of nearly five-fold greater resistance to enteric fever.^[2] This strong association underscores the importance of HLA class II variations in shaping the immune response to Salmonella bacteria, likely by influencing the efficiency of antigen presentation and subsequent T-cell activation. Interestingly, the minor allele of *rs7765379 *has also been linked to increased susceptibility to certain autoimmune conditions, such as Crohn’s disease and rheumatoid arthritis, highlighting a potential evolutionary trade-off between robust immunity against pathogens and the risk of autoimmunity.^[2] Beyond classical immune genes, long intergenic non-coding RNAs (lincRNAs) such as LINC03000 and LINC01938are increasingly recognized for their regulatory roles in immune function. These non-protein-coding RNA molecules, typically over 200 nucleotides in length, can influence gene expression through various mechanisms, including chromatin remodeling, transcriptional interference, and acting as molecular sponges for microRNAs. A single nucleotide polymorphism like*rs143977447 *, if located within or near these lincRNA genes, could potentially alter their expression levels, stability, or interaction with other cellular components. Such alterations could, in turn, modulate immune pathways involved in the host response to bacterial infections like typhoid fever, affecting outcomes such as inflammation, cytokine production, or immune cell differentiation. Host genetic factors, including those involving lincRNAs, are known to play a critical role in determining susceptibility to infectious diseases.^[2] Understanding the precise mechanisms through which variants like *rs143977447 *influence these lincRNAs could provide novel insights into the genetic basis of typhoid fever resistance or susceptibility.^[2]

Key Variants

RS ID	Gene	Related Traits
rs7765379	MTCO3P1 - HLA-DQB3	rheumatoid arthritis Crohn’s disease typhoid fever
rs143977447	LINC03000 - LINC01938	typhoid fever dysentery gastroenteritis

Definition and Etiological Classification

Typhoid fever, also known as enteric fever, is a significant global public health concern, characterized by systemic infection with specific bacterial serovars.^[2] It is estimated to cause millions of new infections and hundreds of thousands of deaths worldwide annually.^[1] The primary causative agents are Salmonella enterica serovar Typhi (S. Typhi) and Salmonella enterica serovar Paratyphi (S. Paratyphi) pathovars, which include S. Paratyphi A, B, and C.^[2]Infection typically occurs through the consumption of food or water contaminated with fecal matter.^[2]

Diagnostic Criteria and Operational Definitions

The diagnosis of typhoid fever relies on a combination of clinical presentation and laboratory confirmation. Research studies often define cases as children or adults exhibiting clinical signs and symptoms of enteric fever, with the definitive diagnosis confirmed by the isolation ofS. Typhi or S. ParatyphiA from blood or bone marrow cultures.^[2]This operational definition, particularly the requirement for blood culture–confirmed infection, is crucial for accurate case ascertainment in clinical trials and epidemiological studies.^[2] While clinical signs are indicative, culture-based methods provide the precise measurement approach for identifying the causative pathogen.

Disease Subtypes and Severity Gradations

Enteric fever encompasses distinct subtypes primarily classified by the infecting Salmonellaserovar: typhoid fever (caused byS. Typhi) and paratyphoid fever (caused by S. Paratyphi). The prevalence of these subtypes can vary geographically, as observed in studies where S. Typhi accounted for over 99% of cases in Vietnam, while S. Paratyphi A comprised a substantial proportion (32%) of cases in Nepal.^[2]Furthermore, the concept of “complicated typhoid fever” implies a gradation of disease severity, highlighting cases with more severe clinical manifestations or outcomes.^[6] The existence of protective vaccines against S. Typhi and the lack of licensed vaccines for S. Paratyphi pathovars also underscore the importance of this etiological classification for public health interventions.^[2]

Clinical Manifestations and Disease Course

Typhoid fever, caused primarily bySalmonella enterica serovar Typhi (S. Typhi), presents with a range of clinical signs and symptoms that can vary in severity and progression. The broader term “enteric fever” encompasses infections caused by both S. Typhi and S. Paratyphi pathovars, with clinical presentations often overlapping.^[2]The disease is recognized as a systemic infection affecting both children and adults, with global estimates pointing to millions of new infections and hundreds of thousands of deaths annually, highlighting a significant severity range.^[2] The progression of symptoms typically leads individuals to seek clinical evaluation for suspected enteric fever.

Diagnostic Approaches and Phenotypic Diversity

The definitive diagnosis of typhoid fever relies on objective measurement approaches, primarily through culture-confirmation of the causative bacteria. Cases are typically confirmed by identifyingS. Typhi or S. Paratyphi Ain blood or bone marrow samples.^[2] Clinical information, including demographic data and observed symptoms, is systematically recorded into case report forms during hospitalization or study participation, providing subjective and observational data to complement laboratory findings.^[2] Phenotypic diversity is observed in the causative agents, with S. Typhi being predominant in certain regions like Vietnam, while S. Paratyphi A contributes a notable proportion of cases in others, such as Nepal.^[2] Although specific age-related symptom variations are not detailed, cases are identified across both pediatric and adult populations.

Host Genetic Influence and Prognostic Indicators

Host genetic factors play a critical role in determining susceptibility and potentially the outcome of typhoid fever, influencing its diagnostic significance and prognostic indicators. For example, specific variations within the human leukocyte antigen (HLA) region, notably theHLA-DRB1*04:05 allele, have been strongly associated with resistance to enteric fever, suggesting a protective role.^[2]This genetic insight highlights the inter-individual variability in disease response, where certain genotypes, such as the minor allele ofrs7765379 near HLA-DQB1 and HLA-DRB1, are under-represented in cases, indicating resistance.^[2] Understanding these host determinants can contribute to identifying individuals at higher risk or those with inherent resistance, offering valuable prognostic information beyond conventional clinical markers.

Causes of Typhoid Fever

Typhoid fever, a systemic infection caused primarily bySalmonella enterica serovar Typhi (S. Typhi) and to a lesser extent by S. enterica serovar Paratyphi (S. Paratyphi) A, B, or C pathovars, is a significant global public health concern, causing millions of infections and hundreds of thousands of deaths annually.^[1]The development and outcome of this disease are influenced by a complex interplay of host genetic factors, environmental exposures, and characteristics of the infecting pathogen.

Genetic Predisposition and Host Immunity

Host genetic factors play a critical role in determining susceptibility or resistance to typhoid fever. A genome-wide association study (GWAS) identified a strong association with a single nucleotide polymorphism (SNP)rs7765379 in the human leukocyte antigen (HLA) class II region, specifically in proximity to the HLA-DQB1 and HLA-DRB1 genes.^[2] The minor allele of rs7765379 was significantly under-represented in enteric fever cases, suggesting a protective effect.^[2] Further fine-mapping revealed that the classical HLA-DRB1 04:05 allele could entirely explain this association, indicating that HLA-DRB1 is a major contributor to resistance, likely through its role in antigen presentation to the immune system.^[2]This protective effect is substantial, offering nearly a 5-fold greater resistance to the disease for individuals carrying this allele.^[2] Beyond the HLA region, another SNP marker, rs6841458 , located near GUCY1A3 on chromosome 4, showed an association with increased susceptibility in the discovery phase; however, this association was not consistently replicated in independent cohorts.^[2] While rare genetic diseases involving mutations in interleukin-12 (IL-12) or interferon-gamma (IFN-γ) pathways are known to cause hypersusceptibility to non-typhoidal Salmonella and other intracellular bacteria, these specific mutations have not yet been definitively linked to enteric fever susceptibility.^[7] Earlier candidate gene studies examining factors like natural resistance-associated macrophage protein 1 (NRAMP1) or other MHC class II and III genes were often limited by small sample sizes, which constrained their ability to identify robust associations.^[8]

Environmental Exposure and Socioeconomic Determinants

The primary mode of transmission for typhoid fever involves the consumption of food or water contaminated with fecal matter containingS. Typhi or S. Paratyphi pathovars.^[2]Consequently, environmental factors, particularly sanitation practices and access to clean water, are paramount in determining disease prevalence. While industrialization and significant improvements in sanitation infrastructure have effectively reduced the burden of typhoid fever in many developed countries, the disease remains endemic in numerous lower-income regions globally.^[3]These socioeconomic disparities, including inadequate public health infrastructure and limited access to safe drinking water and proper waste disposal, contribute substantially to the continued spread and persistence of the disease in vulnerable populations.^[2]

Pathogen Characteristics and Host-Pathogen Dynamics

The interaction between the human host and the bacterial pathogen is a critical determinant of disease outcome. The genetic variability ofS. Typhi itself, along with its specific virulence mechanisms, has been extensively investigated.^[4] Different strains of S. Typhican possess varying capacities to cause severe disease or evade host immune responses. Furthermore, age is a significant contributing factor, as young children represent one of the most at-risk groups for typhoid fever.^[2] Although protective vaccines exist for S. Typhi, their limited efficacy and unsuitability for young children mean they are not widely deployed in the populations most in need.^[5] The absence of a licensed vaccine against S. Paratyphi pathovars, coupled with their increasing incidence in several Asian countries, poses an additional challenge in controlling enteric fever.^[9]

Biological Background of Typhoid Fever

Typhoid fever, also known as enteric fever, is a severe systemic illness caused primarily by the bacteriumSalmonella enterica serovar Typhi (S. Typhi), and less commonly by Salmonella enterica serovar Paratyphi (S. Paratyphi).^[2]This infectious disease remains a significant global public health concern, particularly in lower-income countries where sanitation and clean water access may be limited.^[2]Infection typically occurs through the consumption of food or water contaminated with fecal matter from an infected individual.^[2]The outcome of infection, including disease severity and progression, is influenced by a complex interplay between the pathogen’s virulence and the host’s immune response.^[2]

Pathogen-Host Interaction and Virulence Mechanisms

Upon ingestion, Salmonellabacteria initiate a sophisticated assault on host cells, employing various virulence mechanisms to establish infection and evade immune detection. A critical aspect involves the injection of bacterial-derived effector proteins directly into host cells, such as macrophages, to manipulate cellular functions.^[2] This manipulation influences host cell activation, creating an environment conducive to bacterial survival and replication within the host.^[2] Furthermore, Salmonella utilizes dendritic cells, which are crucial antigen-presenting cells, for systemic dissemination throughout the body, while simultaneously restricting their ability to properly process and present antigens to other immune cells.^[2] The pathogen also employs regulatory networks, such as the yehUT two-component system, which has been characterized in Salmonella enterica serovar Typhi and Typhimurium, to adapt to the host environment and control gene expression essential for virulence.^[10]

Host Immune Response and Antigen Presentation

The human host mounts an intricate immune response against Salmonellainfection, involving both innate and adaptive immunity. A key component of the adaptive immune system’s defense is the major histocompatibility complex (MHC) class II molecules, which are crucial for presenting pathogen-derived antigens toCD4+ T lymphocytes.^[2] Specifically, the HLA-DRB1 gene encodes the beta chain of the HLA-DR molecule, a type of HLA class II protein.^[2] Variations in the HLA-DR region can significantly impact the capacity of these molecules to effectively present antigens, thereby leading to a differential immune response against the invading Salmonella.^[2] An optimal antigen presentation by HLA-DR is essential for activating CD4+T cells, which then coordinate further immune responses to clear the infection.

Genetic Influence on Susceptibility and Resistance

Genetic factors within the human host play a significant role in determining susceptibility or resistance to typhoid fever. A strong association has been found with the human leukocyte antigen (HLA) region, particularly near theHLA-DQB1 and HLA-DRB1 genes.^[2] Notably, the HLA-DRB1*04:05allele has been identified as strongly protective against enteric fever, offering a substantial fivefold greater resistance to the disease.^[2] This protective effect is presumed to occur through enhanced antigen presentation, tipping the balance of pathogenicity in favor of the human host.^[2] While certain rare genetic conditions involving mutations in the interleukin (IL)-12 or interferon (IFN)-γ pathways cause hypersusceptibility to other intracellular bacteria, these specific mutations have not yet been linked to enteric fever susceptibility.^[7]The single nucleotide polymorphism (SNP)rs7765379 , located near HLA-DQB1 and HLA-DRB1, showed a strong association with resistance, which was fully explained by the presence of the HLA-DRB1*04:05 allele.^[2] Another SNP, rs6841458 , near GUCY1A3 on chromosome 4, was also identified, though its association was not consistently replicated across different populations.^[2]

Clinical Manifestations and Systemic Impact

Enteric fever represents the most severe form of Salmonellainfection in humans, characterized by a systemic illness that can lead to significant morbidity and mortality.^[2]Without appropriate antimicrobial treatment, the disease can be fatal in 10-25% of patients.^[2] Even among survivors, those who do not receive timely treatment often experience longer fever clearance times and a higher incidence of severe clinical complications.^[2]The infection disrupts normal homeostatic processes throughout the body as the bacteria disseminate from the gut to various organs, including the liver, spleen, and bone marrow. This systemic spread, coupled with the host’s immune response, contributes to the wide range of symptoms and potential organ-specific effects observed in typhoid fever patients.

Host Immune Recognition and Signaling

The human immune system plays a critical role in determining the outcome of enteric fever, with host genetic factors influencing susceptibility and resistance. A key mechanism involves the Major Histocompatibility Complex (MHC) class II region, particularly the HLA-DRB1 gene. HLA-DRB1 alleles, such as HLA-DRB1*04:05, are associated with resistance to enteric fever, suggesting a central role in antigen presentation to initiate adaptive immune responses.^[2] This process is crucial for the host to recognize Salmonellaantigens and mount an effective defense, highlighting how host receptor activation and subsequent intracellular signaling cascades are pivotal in disease progression.

Beyond HLA-DRB1, other immune signaling pathways are implicated in general susceptibility to intracellular bacteria, including Salmonella. For instance, rare genetic mutations in the IL-12 or IFN-γ pathways can lead to hypersusceptibility to non-typhoidal Salmonella infections.^[7] While these specific mutations have not yet been directly linked to enteric fever susceptibility, they underscore the broader network interactions and hierarchical regulation within the host immune system that govern the response to Salmonella species, involving complex signaling cascades that regulate immune cell activation and effector functions.

Pathogen Virulence Mechanisms and Host Manipulation

Salmonella enterica pathovars, including S. Typhi, employ sophisticated virulence mechanisms to evade host immunity and promote their survival and dissemination. These pathogens inject bacterial-derived effector proteins into host cells, such as macrophages, to directly influence host cell activation and create an environment conducive to bacterial persistence.^[2] This manipulation involves intricate bacterial signaling pathways that modulate host intracellular cascades, essentially hijacking host cellular machinery for the pathogen’s benefit.

Furthermore, Salmonella utilizes host dendritic cells not only for dissemination throughout the host but also actively restricts their ability to process antigens and present peptides.^[2] This strategic interference with antigen presentation pathways represents a critical regulatory mechanism employed by the pathogen to suppress effective host immune responses. Bacterial regulatory systems, such as the yehUT two-component system in Salmonella enterica serovar Typhi and Typhimurium, are also characterized, highlighting the pathogen’s internal mechanisms for adapting to the host environment and orchestrating virulence factor expression.^[10]

Genetic Regulation of Host Susceptibility

Host genetic variability significantly influences an individual’s susceptibility to enteric fever, with specific genetic loci acting as crucial regulatory mechanisms. A genome-wide association study identified a strong association in the class II human leukocyte antigen (HLA) region, where the SNP rs7765379 near the HLA-DQB1 and HLA-DRB1 genes showed a significant association with resistance.^[2] Fine-mapping further implicated the classical HLA-DRB1*04:05 allele as a major contributor to this resistance, suggesting that specific genetic variants in these immune recognition genes provide substantial protection.^[2] This protective effect, evidenced by an approximately five-fold greater resistance for individuals carrying the minor allele, underscores how host gene regulation and specific protein variations, like those in HLA-DRB1, profoundly impact disease outcome.^[2] The identification of such strong genetic determinants, including rs7765379 and HLA-DRB1*04:05, offers valuable insights into disease-relevant mechanisms and potential therapeutic targets for rational vaccine design and other interventions against enteric fever.^[2] While another SNP, rs6841458 , near GUCY1A3 on chromosome 4 was initially identified, its association was less robust in subsequent replication studies.^[2]

Global Burden and Epidemiological Patterns

Typhoid fever, caused primarily bySalmonella enterica serovar Typhi (S. Typhi) and S. Paratyphi pathovars, remains a substantial global public health concern. Annually, an estimated 26.9 million new infections occur worldwide, leading to approximately 200,000 deaths.^[1]While advancements in industrialization, sanitation infrastructure, and access to clean water have significantly reduced the disease burden in many nations, typhoid fever continues to be endemic in numerous lower-income countries.^[3] Epidemiological surveillance reveals geographic variations in the causative agents; for instance, studies in Vietnam found over 99% of cases were infected with S. Typhi, whereas in Nepal, S. Typhi accounted for 68% of cases and S. Paratyphi A for 32%.^[2] Notably, the incidence of S. Paratyphi Ainfection is increasing across many Asian countries, posing a growing challenge given the current lack of a licensed vaccine against this specific serovar.^[5]

Genetic Susceptibility and Cross-Population Comparisons

Large-scale population studies, including genome-wide association studies (GWAS), have elucidated human host genetic determinants influencing susceptibility to enteric fever. A significant GWAS identified a strong association in the HLA class II region with resistance to enteric fever, specifically at rs7765379 , located near the HLA-DQB1 and HLA-DRB1 genes.^[2] In a Vietnamese discovery cohort comprising 432 individuals with culture-confirmed S. Typhiinfection and 2,011 controls, the minor allele ofrs7765379 was significantly under-represented in cases compared to controls (1.04% vs. 5.5%; OR = 0.18, P = 4.5 × 10−10), indicating a protective effect.^[2] This finding was robustly replicated in an independent cohort of 595 enteric fever cases and 386 controls from Nepal, and a second replication in 151 cases and 668 controls from Vietnam, where the minor allele of rs7765379 continued to show under-representation in cases.^[2] Further fine-mapping implicated the classical HLA-DRB1*04:05 allele as entirely explaining the association at rs7765379 , suggesting its critical role in resistance, likely through antigen presentation.^[2] While a second SNP, rs6841458 near GUCY1A3, also showed genome-wide significance in the discovery phase, it did not replicate in the Nepalese cohort.^[2] Cross-population analysis in Nepal, despite greater ancestry diversity among participants compared to the predominantly Vietnamese Kinh cohort, confirmed the association with rs7765379 remained robust after stratification for self-reported ancestry.^[2] Previous candidate gene studies, which examined genes like NRAMP1, TNF region haplotypes, or specific HLA-DRB1alleles, were often limited by sample size and statistical power, highlighting the advantage of large-scale GWAS in identifying robust genetic associations.^[8]

Methodological Approaches and Generalizability

Population studies on typhoid fever employ rigorous methodologies to ensure the reliability and generalizability of findings. The large-scale genetic studies, for instance, defined cases as children or adults presenting with clinical signs and symptoms of enteric fever, confirmed by blood or bone marrow culture forS. Typhi or S. Paratyphi A.^[2] Control populations were carefully selected, utilizing cord blood samples from geographically matched newborns to represent the general population, with significant sample sizes (e.g., 2,011 Vietnamese controls for discovery, 386 Nepalese controls, and 668 Vietnamese controls for replication).^[2] Clinical studies were conducted over extended periods, such as 1992-2002 in Vietnam across multiple hospitals and 2005-2014 at Patan Hospital in Kathmandu, Nepal, allowing for comprehensive data collection.^[2] Genetic analyses employed advanced techniques like Illumina BeadChips for initial genotyping and TaqMan assays for replication, with stringent quality control measures to filter out poor-performing samples and SNPs.^[2] To address potential confounding from population stratification, principal-component analysis was used, and logistic regression models were adjusted for the first ten principal components.^[2] The replication stages were sufficiently powered to detect modest to strong genetic effects, enhancing the confidence in the identified associations.^[2] Ethical approvals from relevant committees and informed consent from participants or their guardians were paramount in all study phases, ensuring the responsible conduct of research.^[2]

Frequently Asked Questions About Typhoid Fever

These questions address the most important and specific aspects of typhoid fever based on current genetic research.

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1. Why do some people get typhoid easily, but my friends don’t?

Your genetics play a big role in how susceptible you are to typhoid fever. Research shows that certain genetic markers, particularly in a region calledHLA-DRB1, can offer significant protection. For example, having a specific variant, like HLA-DRB104:05, can make you nearly five times more resistant to the infection compared to others, meaning some are naturally better equipped to fight it off.

2. If my family gets typhoid easily, will I too?

It’s possible, as genetic factors influencing typhoid resistance can be inherited. If your family members share certain genetic predispositions, like particular HLA-DRB1 alleles that don’t offer strong protection, you might have a similar genetic makeup. However, exposure to contaminated food or water is also crucial, so even with a genetic predisposition, good hygiene and safe food practices are vital.

3. Can my genes actually protect me from getting typhoid?

Yes, your genes can indeed offer a strong level of protection. A specific genetic variant, HLA-DRB104:05, has been identified as providing nearly a five-fold greater resistance to typhoid fever. This means your body’s immune system, guided by your genetics, is much more effective at fighting off theSalmonella bacteria if you carry this protective allele.

4. Does my background affect my typhoid risk?

Yes, your genetic background can influence your risk. Studies have shown that genetic factors for typhoid resistance can vary across different populations. While a specific protective gene variant has been identified, its frequency and the overall genetic architecture for resistance might differ based on your ethnic and geographical ancestry.

5. Could a DNA test help me decide on a typhoid vaccine?

Potentially, yes. Understanding your individual genetic profile, particularly in the HLA class II region, could inform vaccine decisions in the future. Researchers are exploring how variations in genes like HLA-DRB1 could be used to design more effective vaccines. While not currently a standard practice, personalized genetic information might one day help determine your specific need or the best vaccine strategy for you.

6. Can I overcome my genes by being super careful with food?

Absolutely, yes! While genetics play a significant role in susceptibility, typhoid fever is primarily transmitted through contaminated food and water. Being meticulous about hygiene, ensuring food safety, and drinking clean water are crucial preventative measures that can significantly reduce your risk, regardless of your genetic predisposition. Environmental factors and exposure are key.

7. Does it matter if I get one type of typhoid bacteria versus another?

Yes, it can matter. Typhoid fever is caused byS. Typhi, but also by S. Paratyphi pathovars. While genetic resistance markers like rs7765379 near HLA-DRB1 seem to be broadly protective, the genetic basis for resistance might not be identical across all these different Salmonella serovars. Also, there’s currently no licensed vaccine against S. Paratyphi, which is a growing concern.

8. Why aren’t typhoid vaccines better for everyone, especially kids?

Current vaccines against S. Typhi have limited efficacy and aren’t suitable for young children, who are often the most vulnerable. This restricts their widespread adoption, especially in areas where they are most needed. Additionally, there’s no licensed vaccine yet for S. Paratyphi. Research into genetic variation, like in the HLA region, is hoped to lead to more effective vaccine designs in the future.

9. If I travel to typhoid areas, does my body fight it differently?

Yes, your body’s immune response can indeed be different due to your genetics. Even when traveling to areas where typhoid is common, some individuals possess genetic variants, like HLA-DRB104:05, that significantly enhance their natural resistance. This means their immune system is better equipped to recognize and fight off the Salmonellabacteria upon exposure, potentially preventing infection or reducing severity.

10. Do typhoid gene findings apply to people like me in my country?

The main genetic findings, like the protective effect of HLA-DRB104:05, are significant globally. However, the initial studies were primarily conducted in specific populations from Vietnam and Nepal. While these findings are a major step, the exact genetic architecture of resistance might vary across different ethnic and geographical groups, so further research is needed to fully understand how these apply universally.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Buckle GC, et al. “Typhoid fever and paratyphoid fever: systematic review to estimate global morbidity and mortality for 2010.”J. Glob. Health, vol. 2, 2012, p. 010401.

[2] Dunstan, S. J., et al. “Variation at HLA-DRB1 is associated with resistance to enteric fever.” Nat Genet, vol. 46, no. 12, 2014, pp. 1322-25.

[3] Cvjetanović B, et al. “Epidemiological model of typhoid fever and its use in the planning and evaluation of antityphoid immunization and sanitation programmes.”Bull. World Health Organ., vol. 45, 1971, pp. 53–75.

[4] Kingsley RA, et al. “Genome and transcriptome adaptation accompanying emergence of the definitive type 2 host-restricted Salmonella enterica serovar Typhimurium pathovar.” MBio., vol. 4, 2013, p. e00565–13.

[5] McGregor AC, et al. “Prospects for prevention of Salmonella infection in children through vaccination.”Curr. Opin. Infect. Dis., vol. 26, 2013, pp. 254–262.

[6] Dharmana, E., et al. “HLA-DRB1*12 is Associated with Protection Against Complicated Typhoid Fever, Independent of Tumour Necrosis Factor α.”European Journal of Immunogenetics, vol. 29, no. 4, 2002, pp. 297–300.

[7] de Jong R, et al. “Severe mycobacterial and Salmonella infections in interleukin-12 receptor–deficient patients.” Science, vol. 280, 1998, pp. 1435–1438.

[8] Dunstan, S. J., et al. “Genes of the class II and class III major histocompatibility complex are associated with typhoid fever in Vietnam.”J. Infect. Dis., vol. 183, 2001, pp. 261–268.

[9] Karki S, et al. “Trends of etiology and drug resistance in enteric fever in the last two decades in Nepal: a systematic review and meta-analysis.” Clin. Infect. Dis., vol. 57, 2013, pp. e167–e176.

[10] Wong VK, et al. “Characterization of the yehUT two-component regulatory system of Salmonella enterica serovar Typhi and Typhimurium.” PLoS ONE, vol. 8, 2013, p. e84567.