Shigellosis
Introduction
Section titled “Introduction”Shigellosis, an acute intestinal infection caused by bacteria of the genusShigella, is a major global health challenge, recognized as a leading cause of moderate-to-severe diarrhea and bacillary dysentery. Annually, it is associated with an estimated 80 to 165 million cases of diarrhea worldwide.[1]
Biological Basis
Section titled “Biological Basis”Shigella are Gram-negative, rod-shaped bacteria that invade the epithelial cells of the colon, leading to intense inflammation and tissue damage. A key mechanism of Shigella virulence involves its Type 3 Secretion System (T3SS), a needle-like apparatus that injects bacterial effector proteins directly into host cells. These effectors manipulate various host cellular processes, including cytoskeletal dynamics and immune responses, enabling bacterial invasion, intracellular multiplication, and spread to adjacent cells.[1] Host genetic factors, particularly those affecting bacterial T3SS activity and the host immune response, are increasingly recognized for their role in determining susceptibility to Shigella-associated diarrhea.[1]
Clinical Relevance
Section titled “Clinical Relevance”Clinically, shigellosis presents with symptoms such as watery or bloody diarrhea, fever, and abdominal cramps. Beyond the acute illness,Shigella infections can have severe long-term consequences, especially in infants and young children. These include elevated rates of stunting (growth faltering), increased inflammatory markers, and potential adverse effects on the cellular architecture of gastrointestinal tissues and cognitive development.[1] Research indicates that host genetic variations can significantly influence an individual’s susceptibility to Shigellainfection and the severity of the disease.[1]
Social Importance
Section titled “Social Importance”The global burden of shigellosis is substantial, particularly in regions with poor sanitation and hygiene. While prompt oral rehydration and antibiotic therapy are crucial for treatment, the rising prevalence of drug-resistantShigella strains in high-burden areas poses a significant threat to public health. This growing antibiotic resistance underscores the urgent need for effective preventive measures, including vaccine development and improved hygiene practices. Understanding the complex interplay between host genetic factors and Shigellapathogenesis is vital for developing new diagnostic tools, therapeutic strategies, and vaccines to combat this widespread infectious disease.[1]
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”The discovery of genetic loci associated with shigellosis susceptibility is subject to several methodological and statistical limitations. The study relied on a meta-analysis combining two independent cohorts, totaling 143 cases and 443 controls, which represents a limited sample size for a genome-wide association study (GWAS).[1] While meta-analysis aims to enhance statistical power, small sample sizes inherently carry a risk of reduced power to detect true associations and may lead to inflated effect sizes for identified variants. Furthermore, the application of a conservative Bonferroni correction-based P value threshold, while mitigating the risk of Type I errors, potentially increases the likelihood of Type II errors, meaning some genuine genetic associations might have been overlooked.[1] The analysis was also restricted to variants with a minor allele frequency of at least 0.5%, excluding rarer genetic variations that could contribute to susceptibility.
Another notable limitation pertains to the functional interpretation of the identified genetic variants. Despite identifying several genome-wide significant loci, no variant of known function was observed directly at these primary loci.[1] Subsequent expression quantitative trait locus (eQTL) analysis, specifically querying the top variants and nearby linked variants within gastrointestinal tissues from the GTEx database, did not reveal any associations with the mRNA expression of nearby genes.[1]This absence of direct functional evidence for the top hits means that the precise biological mechanisms by which these variants influence shigellosis susceptibility remain largely unconfirmed, highlighting a gap in understanding their downstream effects on gene regulation.
Generalizability and Phenotype Definition
Section titled “Generalizability and Phenotype Definition”The generalizability of these findings is primarily limited by the study’s design, which focused exclusively on two birth cohorts of Bangladeshi infants in Dhaka.[1] While this population exhibited no evidence of internal genetic stratification, the results may not be directly transferable to populations of different ancestries or geographical regions, where genetic backgrounds, environmental exposures, and host-pathogen interactions might vary significantly. The study specifically investigated infant susceptibility within the first 13 months of life, meaning the identified genetic factors might not exert the same influence or even be relevant in older children or adult populations, who may have different immune responses or exposure patterns.
The definition of “Shigella-associated diarrhea” was based on quantitative PCR (qPCR) detection of theipaH gene.[1]While a robust molecular method for pathogen identification, this phenotypic characterization may not fully capture the clinical spectrum or varying severity of shigellosis. Although diarrheal severity, measured via the Ruuska score, was included as a covariate, the study’s focus on pathogen presence rather than broader clinical outcomes might limit the comprehensive understanding of how host genetics influence the disease course or severity beyond initial susceptibility.
Unexplored Factors and Remaining Knowledge Gaps
Section titled “Unexplored Factors and Remaining Knowledge Gaps”The complex interplay between host genetics and environmental factors in shigellosis susceptibility represents a significant area of remaining knowledge gaps. The research acknowledges thatShigellaexposure is widespread, yet infection is heterogeneous.[1]suggesting that while host genetic factors play a crucial role, other unmeasured or unaddressed environmental variables likely contribute to the observed variability in disease outcomes. Factors such as specific dietary components, co-infections with other enteropathogens, hygiene practices, and the precise level or duration ofShigella exposure were not explicitly detailed as limitations in their influence on genetic associations.
Furthermore, despite identifying several genetic loci, the direct functional consequences of these variants are not fully elucidated. While the identified loci were indirectly linked to bacterial Type III Secretion System (T3SS) activity.[1]the specific molecular pathways or changes in protein function mediated by the associated single nucleotide polymorphisms (SNPs) remain to be definitively established. The absence of eQTL associations for the top hits implies that their impact might not be through simple changes in gene expression in the tested tissues, suggesting more complex regulatory mechanisms or effects in tissues not analyzed, which contributes to the “missing heritability” and overall knowledge gap in the pathogenesis of shigellosis.
Variants
Section titled “Variants”Several genetic variants are associated with infant susceptibility to Shigella-associated diarrhea, influencing host defense mechanisms that interact with bacterial pathogenesis. Key variants have been identified in genes involved in cytoskeletal integrity, gene regulation, and cellular trafficking, all playing a role in the host’s response toShigellainfection.
The variant rs582240 is located within KRT18P59, a transcribed pseudogene that shares substantial sequence identity with KRT18 (keratin 18). Keratins are essential proteins that provide structural support to epithelial cells, protecting them from damage and stress, and contributing to overall cytoskeletal integrity.[1] The T allele of rs582240 is associated with a reduced risk of Shigella-associated diarrhea, indicating a protective effect. This variant acts as a cis-eQTL, linked to increased expression ofKRT18P59across various tissues, which may mitigate shigellosis risk by potentially interfering with normalKRT18 function or its interaction with Shigella-derived proteins like IpaC at the epithelial cell surface, both critical for bacterial invasion.[1] Another protective variant, rs12550437 , is found within RP11-115J16.1, a long intergenic noncoding RNA (lincRNA). LincRNAs are known to modulate gene expression through various mechanisms, including transcriptional regulation and chromatin remodeling.[1] rs12550437 functions as a cis-eQTL, associated with reduced expression of PRAG1 (PEAK1 related, kinase-activating pseudokinase 1) in thyroid tissue. PRAG1 is implicated in regulating Src family kinase (SFK) activity, which is crucial for efficient bacterial invasion by Shigella.[1] A potential mechanism for its protective effect could involve reduced sequestration of the SFK inhibitor Csk, thereby limiting the membrane-bound SFK activity that Shigella requires for efficient entry into host cells.
The variant rs10266841 , situated in the 3’ untranslated region (UTR) of the CYTH3 gene, represents another protective genetic factor against Shigella-associated diarrhea.[1] CYTH3 (cytohesin-3) is a widely expressed protein that plays a critical role in regulating protein sorting and membrane trafficking within cells, and it may also be involved in regulating ADP-ribosylation factor proteins.[1] This variant is predicted to be “possibly damaging” to CYTH3 function, suggesting that altered CYTH3 activity might hinder Shigella pathogenesis. The protective effect observed with rs10266841 is potentially linked to its influence on bacterial Type 3 Secretion System (T3SS) activity, a key virulence mechanism for Shigella.[1] The protective effect of rs10266841 became even more pronounced in conditional meta-analyses, underscoring its significant role in infant susceptibility to shigellosis.[1]
Key Variants
Section titled “Key Variants”Defining Shigellosis: Etiology and Clinical Presentation
Section titled “Defining Shigellosis: Etiology and Clinical Presentation”Shigellosis is an infectious disease caused by bacteria of the genusShigella, which are Gram-negative, rod-shaped microorganisms.[1]It is recognized as a leading global cause of moderate-to-severe diarrhea and is specifically the causative agent of bacillary dysentery, a more severe form characterized by bloody stools.[1]This enteric infection contributes significantly to the global burden of diarrheal disease, accounting for an estimated 80 to 165 million cases annually.[1], [2]Beyond acute illness, shigellosis carries substantial long-term health implications, particularly in vulnerable populations such as infants. Infections are associated with elevated rates of stunting and increased inflammatory markers, which can have adverse effects on the cellular architecture of gastrointestinal tissues and cognitive development.[1], [3]Effective treatment for shigellosis typically involves prompt oral rehydration and antibiotics.[1] However, the rising prevalence of drug resistance in high-burden areas underscores the critical importance of preventive measures, with vaccination being considered the most effective method for reducing Shigella-associated morbidity and mortality globally.[1] While exposure to Shigellacan be ubiquitous in many regions, symptomatic disease develops in only a subset of individuals, suggesting an interplay of environmental factors like hygiene and host susceptibility, including potential immunogenetic roles.[1], [4]
Classification of Shigellaand Disease Severity
Section titled “Classification of Shigellaand Disease Severity”The Shigellagenus comprises four main species that are recognized causative agents of shigellosis:S. dysenteriae, S. flexneri, S. boydii, and S. sonnei.[1]These species vary in their geographical distribution and epidemiological patterns, contributing to the diverse clinical manifestations of shigellosis. The identification of specificShigella species is crucial for epidemiological tracking and guiding treatment strategies, especially given evolving patterns of antibiotic resistance.
Disease severity in shigellosis can be assessed through various clinical and anthropometric measures. The Ruuska score is one method used to quantify the severity of diarrheal events.[1] Beyond immediate symptoms, the long-term impact on growth is a critical severity indicator, with Shigella cases often exhibiting lower height-for-age z-scores (HAZ) and weight-for-age z-scores (WAZ) compared to controls.[1]These anthropometric z-scores, standardized against World Health Organization reference populations, provide a comprehensive view of growth faltering associated with the disease.[1]
Diagnostic and Research Criteria for Shigellosis
Section titled “Diagnostic and Research Criteria for Shigellosis”Precise diagnosis of shigellosis in clinical and research settings primarily relies on the detection ofShigella through molecular methods. Quantitative Polymerase Chain Reaction (qPCR) is a key measurement approach, enhancing the ascertainment of Shigellaburden, particularly in children with moderate-to-severe diarrhea.[5] For research purposes, a case of Shigella-associated diarrhea is operationally defined by at least one diarrheal event positive forShigella with a qPCR Cycle Threshold (CT) value of less than 30 within a specific timeframe, such as the first 13 months of life.[1] This CT threshold of <30 is considered a conservative measure, indicating a higher bacterial load compared to the broader global threshold often used for Shigella-associated stool samples, which is typically <33.1.[1] Conversely, controls are defined as individuals who do not meet these criteria, typically exhibiting CT values greater than 30.[1] The ipaH gene, which encodes a protein involved in Shigella invasion, serves as a specific molecular target for qPCR assays, and its detection helps confirm the presence of pathogenic Shigella species like S. flexneri or S. sonnei.[1]
Core Clinical Manifestations
Section titled “Core Clinical Manifestations”Shigellosis, primarily caused byShigellabacteria, is a leading global cause of moderate-to-severe diarrhea and is the causative agent of bacillary dysentery.[1]The hallmark symptom is diarrhea, characterized by an increased frequency of diarrheal events. Individuals diagnosed with shigellosis experience, on average, a higher number of diarrheal episodes compared to unaffected individuals, with reported averages ranging from 4.4 to 5.4 events in cases versus 3.3 to 3.6 in controls.[1] In infants, the initial Shigella-associated diarrheal event typically manifests between 115 and 154 days after their first-ever diarrheal episode.[1] It is also common for Shigella-associated diarrheal events to occur as co-infections, with enteroaggregative Escherichia coli (EAEC) frequently detected alongside Shigella in at least half of identified cases.[1]
Disease Severity and Assessment
Section titled “Disease Severity and Assessment”The severity of diarrheal events in shigellosis can be quantitatively evaluated using specific assessment methods, such as the Ruuska score.[1]This objective measurement tool helps characterize the spectrum of disease presentation. WhileShigellainfections are generally associated with moderate-to-severe diarrhea, the average Ruuska score for diarrheal events can exhibit variability across different populations. For instance, in one cohort,Shigella cases had a slightly lower average Ruuska score (6.9) for their diarrheal events compared to controls (7.4), suggesting that their overall diarrheal episodes were, on average, less severe.[1] Conversely, in another cohort, the average Ruuska scores between cases (10.5) and controls (10.2) did not significantly differ.[1] The diagnostic significance of assessing severity lies in guiding appropriate clinical management, including prompt oral rehydration and antibiotic therapy, especially given the rising prevalence of drug resistance.[1]
Long-term Complications and Individual Heterogeneity
Section titled “Long-term Complications and Individual Heterogeneity”Beyond acute symptoms, Shigella infections are linked to notable long-term adverse health outcomes. These include elevated rates of stunting at the population level and increased inflammatory markers, which can lead to lasting damage to the cellular architecture of gastrointestinal tissues and impair cognitive development.[1] Although not always statistically significant, Shigella cases have been observed to have lower height-for-age z-score (HAZ) values at both one week and one year of life compared to controls, indicating a potential for linear growth faltering.[1] Significant heterogeneity exists in susceptibility to symptomatic Shigellainfection, as exposure is widespread, yet only a subset of individuals develops overt disease.[1] Host genetic factors contribute to this variability, with protective genetic loci identified on chromosome 11 (rs582240 in KRT18P59) and chromosome 8 (rs12550437 in RP11-115J16.1).[1] Additionally, conditional genetic analyses have uncovered a protective locus on chromosome 7 (rs10266841 within the 3’ UTR of CYTH3) and a risk-associated locus on chromosome 10 (rs2801847 , an intronic variant within MPP7), all indirectly associated with bacterial type 3 secretion system (T3SS) activity.[1]While one small study suggested an increased risk of shigellosis for individuals with ABO blood group B, this association was not consistently observed in larger cohorts.[1]
Causes
Section titled “Causes”Shigellosis, an acute intestinal infection caused byShigellabacteria, results from a complex interplay of host genetic susceptibility and environmental factors. While exposure to the pathogen is common in many regions, the development of symptomatic disease exhibits significant heterogeneity, highlighting the importance of individual predispositions.[1] Understanding these causal factors is crucial for developing effective prevention and treatment strategies.
Genetic Predisposition
Section titled “Genetic Predisposition”Host genetic factors play a significant role in determining an individual’s susceptibility to Shigella-associated diarrhea. Genome-wide association studies (GWAS) have identified several genetic loci linked to infant susceptibility. For instance, protective loci includers12550437 within the lincRNA RP11-115J16.1 on chromosome 8, rs582240 within the pseudogene KRT18P59 on chromosome 11, and rs10266841 within the 3’ untranslated region (UTR) of CYTH3 on chromosome 7.[1]Individuals carrying a higher number of these protective alleles demonstrate significantly reduced odds of developing shigellosis.[1] Conversely, a risk-associated locus, rs2801847 , an intronic variant within MPP7 on chromosome 10, has been identified.[1] Both the CYTH3 and MPP7 variants are predicted to be “possibly damaging” to their respective genes.[1] These identified genetic variants are indirectly linked to the activity of the bacterial type 3 secretion system (T3SS), which is critical for Shigella invasion and pathogenesis.[1] Furthermore, certain ABOblood group antigens may influence risk, with studies suggesting individuals with blood group B have an increased susceptibility to shigellosis.[4] Exploration of expression quantitative trait loci (eQTLs) reveals that some associated variants, such as those near KRT18P59, RP11-115J16.1, and CYTH3, likely alter the RNA expression of their overlapping or nearby genes.[1] Specifically, variants on chromosome 10 are associated with reduced MASTL and increased LINC00202-1 mRNA expression, both genes related to the cytoskeletal integrity of host cells, a pathway critical for how Shigella manipulates host cells.[1]
Environmental and Lifestyle Influences
Section titled “Environmental and Lifestyle Influences”Environmental factors and lifestyle practices are primary drivers ofShigellatransmission and infection.Shigella exposure is often ubiquitous in high-burden areas, particularly in developing countries like Bangladesh where studies on infant susceptibility have been conducted.[1] Poor hygiene practices within the household are a well-established risk factor, facilitating the fecal-oral spread of the bacteria.[6] Inadequate sanitation and contaminated water sources are implicit in such environments, further contributing to widespread exposure.
Dietary practices, specifically non-exclusive infant breastfeeding, also increase the risk of shigellosis in infants.[7]Breastfeeding provides protective antibodies and beneficial microbiota, and its absence or reduction can leave infants more vulnerable to enteric pathogens. These environmental and lifestyle factors collectively create conditions conducive toShigellatransmission and infection, particularly in vulnerable populations.
Gene-Environment Interactions
Section titled “Gene-Environment Interactions”The development of shigellosis is not solely determined by exposure or genetics but often arises from complex gene-environment interactions. Despite widespread exposure toShigellabacteria, only a subset of individuals develops symptomatic disease, indicating that host genetic factors modify the response to environmental triggers.[1] For example, host genetic variations that affect bacterial T3SS activity or the integrity of the host cell cytoskeleton can interact with the presence of Shigella to influence invasion and pathogenesis.[1] Genetic predispositions can modulate the host’s immune response or cellular defenses against the pathogen, making some individuals more resilient even when exposed to the bacteria in challenging environments. The interplay between genetic variants impacting epithelial tight junction formation, tyrosine kinase activity, or cytoskeletal structure, and the Shigella T3SS-mediated docking at these junctions, represents a key area of gene-environment interaction.[1]These interactions explain much of the observed heterogeneity in disease outcomes among exposed populations.
Developmental, Epigenetic, and Other Contributing Factors
Section titled “Developmental, Epigenetic, and Other Contributing Factors”Age is a significant contributing factor, with infants exhibiting particular susceptibility to Shigella-associated diarrhea, especially within the first 13 months of life.[1]This heightened vulnerability in early life underscores the importance of developmental stage in disease manifestation. While not explicitly detailed as epigenetic modifications like DNA methylation or histone alterations, the identified lincRNAs, such as RP11-115J16.1 and LINC00202-1, influence gene expression, which can be part of broader gene regulation mechanisms that include epigenetic processes.[1]These regulatory changes may impact cellular responses to infection, thereby influencing susceptibility.
Furthermore, the overall health and developmental status of an individual can modulate the severity and impact of shigellosis.Shigella infections are known to contribute to elevated rates of stunting, increased inflammatory markers, and long-term adverse effects on gastrointestinal tissues and cognitive development.[3]While these are often consequences of shigellosis, a compromised developmental state or pre-existing conditions (e.g., environmental enteropathy in developing countries) could potentially predispose individuals to more severe infections or complicate recovery, highlighting the cyclical nature of health challenges in vulnerable populations.
Shigella Pathogenesis and Disease Manifestation
Section titled “Shigella Pathogenesis and Disease Manifestation”Shigellosis is a diarrheal disease caused byShigella, a genus of Gram-negative rod-shaped bacteria, and is a leading cause of bacillary dysentery and moderate-to-severe diarrhea globally.[1]This infection is a major contributor to worldwide morbidity and mortality, particularly in regions with limited resources. Beyond the acute symptoms,Shigella infections are linked to long-term adverse health outcomes, including elevated rates of stunting, increased inflammatory markers, and potential damage to the cellular architecture of gastrointestinal tissues.[3]These chronic effects can also impact cognitive development and potentially reduce the effectiveness of mucosal vaccines, highlighting the systemic and enduring consequences of the disease.[3]
Host-Pathogen Interactions: The Type III Secretion System
Section titled “Host-Pathogen Interactions: The Type III Secretion System”A critical virulence mechanism employed by Shigella is its Type III Secretion System (T3SS), which acts like a molecular syringe to inject bacterial effector proteins and virulence factors directly into host epithelial cells.[1]This system is indispensable for bacterial invasion and the overall pathogenesis of shigellosis, enablingShigella to manipulate host cellular processes, including transcriptional regulation and chromatin remodeling.[1] The T3SS effector protein IpaC is particularly significant in this process, and targeting components of this pathogen secretion system represents a promising strategy for developing new interventions against Shigella-associated diseases.[1] The T3SS orchestrates a complex interplay with various host biomolecules to facilitate bacterial entry and spread within the host. Shigella induces the recruitment of host tyrosine kinase receptors and triggers tyrosine phosphorylation within cellular protrusions, which are then resolved into vacuoles and subsequently engulfed by neighboring cells.[8] Key host tyrosine kinases, such as Abl, Arg, and Bruton’s tyrosine kinase (Btk), are activated upon Shigellainfection and accumulate at bacterial entry sites to promote invasion.[9] Specifically, Btk phosphorylates the host Wiskott-Aldrich syndrome protein (N-WASP), forming a complex with the Shigella protein IcsA, which is crucial for actin tail formation, bacterial motility, and efficient invasion.[10]
Host Cellular Responses and Cytoskeletal Dynamics
Section titled “Host Cellular Responses and Cytoskeletal Dynamics”Shigella’s pathogenesis relies heavily on its ability to manipulate the host cell’s cytoskeleton and epithelial tight junctions, which serve as primary targets for bacterial entry and T3SS-mediated virulence.[1] Host genetic factors that influence the integrity of the cytoskeleton, including variants in genes associated with keratins, long intergenic non-coding RNAs (lincRNAs), and MASTL, are linked to susceptibility to Shigella-associated diarrhea.[1] Keratins, exemplified by KRT18 and its pseudogene KRT18P59, are structural proteins vital for protecting cells from stress and damage, while also maintaining the cytoskeletal integrity of epithelial cells.[11]The microtubule-associated serine/threonine kinase-like protein (MASTL), a crucial regulator of mitosis and genomic stability, and the lincRNA LINC00202-1 are also integral to cytoskeletal integrity, with their expression levels being affected by Shigella-associated genetic variants.[1] Variations in these host components can lead to altered control of epithelial tight junction formation, modified tyrosine kinase activity, and changes in overall cytoskeletal structure, thereby influencing Shigella’s T3SS-mediated docking and invasion.[1] Furthermore, Shigellacan induce significant alterations in gut epithelial physiology and tissue invasion by disrupting host intracellular transport pathways, involving proteins such as ARF6.[12]
Genetic Modulators of Susceptibility
Section titled “Genetic Modulators of Susceptibility”Host genetic factors play a significant role in determining an individual’s susceptibility to shigellosis, explaining some of the observed heterogeneity in disease outcomes even in areas with widespread exposure.[1]For example, the ABO blood group antigens have been identified as a potential risk factor, with studies indicating an increased risk of shigellosis in individuals with blood group B, suggesting an immunogenetic component to host susceptibility.[4] Genome-wide association studies (GWAS) have pinpointed specific genetic loci associated with infant susceptibility to Shigella-associated diarrhea. These include a protective locus on chromosome 7,rs10266841 , located within the 3’ untranslated region (UTR) of CYTH3, and a risk-associated intronic variant on chromosome 10, rs2801847 , within MPP7.[1] Other significant loci include rs12550437 , located near the lincRNA RP11-115J16.1, and rs582240 , found within the pseudogene KRT18P59.[1] Each of these variants has been indirectly linked to the activity or components of the bacterial T3SS, implying that host genetic variations can critically influence the immune response and cellular pathways essential for Shigella invasion and pathogenesis.[1]
Host-Pathogen Signaling and Kinase Cascades
Section titled “Host-Pathogen Signaling and Kinase Cascades”Shigella pathogenesis is driven by intricate signaling crosstalk with host cells, primarily through its Type III Secretion System (T3SS) which injects effector proteins to manipulate host kinase cascades. Host tyrosine kinases such as Abl and Arg are activated by Shigellainfection and recruited to bacterial entry sites, where they are required for efficient bacterial invasion . Beyond acute illness,Shigella infections are linked to elevated rates of stunting at the population level and increased inflammatory markers, which can lead to long-term adverse effects on gastrointestinal tissues and cognitive development.[3]Population-level studies have identified several key risk factors for shigellosis, including non-exclusive infant breastfeeding and poor household hygiene practices.[7]Longitudinal cohort studies in Bangladesh, such as the PROVIDE and CBC cohorts, have provided detailed insights into the burden of shigellosis in infants. Within their first 13 months of life, 20% of infants in the PROVIDE cohort and 31% in the CBC cohort experienced at least oneShigella-associated diarrheal event.[1]Cases of shigellosis in both cohorts were observed to have a higher average number of diarrheal events compared to controls (e.g., 4.4 vs. 3.6 in PROVIDE cases and controls, respectively).[1] The average age at the first Shigella-associated diarrheal event was approximately 257 days in PROVIDE and 282 days in CBC, indicating a significant burden during infancy.[1]
Host Genetic Susceptibility and Longitudinal Findings
Section titled “Host Genetic Susceptibility and Longitudinal Findings”Large-scale cohort studies combined with advanced genetic analyses have begun to unravel the host factors influencing susceptibility to shigellosis. The PROVIDE and CBC cohorts, consisting of infants from Bangladesh, were utilized in a genome-wide association study (GWAS) to identify genetic loci associated withShigella-associated diarrhea.[1] This meta-analysis, combining data from 143 cases and 443 controls across millions of genetic variants, identified two genome-wide significant associations.[1] Specifically, a protective allele (T allele) at rs582240 within the transcribed processed pseudogene KRT18P59 on chromosome 11 was identified, with a meta-analysis odds ratio (ORMETA) of 0.43 and a P-value of 6.40 × 10^-8.[1] Another protective allele (A allele) was found at rs12550437 within the long intergenic noncoding RNA RP11-115J16.1 on chromosome 8, showing an ORMETA of 0.48 and a P-value of 1.49 × 10^-7.[1] Further conditional analyses also revealed suggestive loci on chromosomes 7 (rs10266841 within CYTH3) and 10 (rs2801847 within MPP7).[1]While a smaller study had suggested an increased risk of shigellosis for individuals with ABO blood group B, this association was not observed in the larger PROVIDE cohort.[4]
Cross-Population Comparisons and Methodological Considerations
Section titled “Cross-Population Comparisons and Methodological Considerations”Population studies on shigellosis employ various methodologies to understand disease patterns and host interactions. The aforementioned GWAS utilized a longitudinal birth cohort design, following infants for their first 13 months of life, and included quantitative PCR (qPCR) for preciseShigella detection, with cases defined by a qPCR CT value of less than 30.[5] Anthropometric measurements, such as weight-for-age Z-scores (WAZ) and height-for-age Z-scores (HAZ), were derived using WHO reference populations to assess nutritional status, although differences in HAZ between cases and controls were not statistically significant.[1] The study adjusted for several covariates, including WAZ, HAZ, diarrheal severity (assessed via Ruuska score), and sex, to account for potential confounding factors.[1] To enhance statistical power and address the relatively limited sample sizes of independent cohorts, a meta-analysis was performed using an inverse-variance method under a fixed-effects additive model.[1] While this robust approach helped identify genetic associations, the findings are primarily specific to the Bangladeshi infant populations studied, highlighting the importance of considering geographic and ethnic variations in susceptibility to infectious diseases.[1]
Frequently Asked Questions About Shigellosis
Section titled “Frequently Asked Questions About Shigellosis”These questions address the most important and specific aspects of shigellosis based on current genetic research.
1. Why did my friend get sick from shigella but I didn’t, even though we ate the same food?
Section titled “1. Why did my friend get sick from shigella but I didn’t, even though we ate the same food?”It’s common for people to react differently to the same exposure. Your unique genetic makeup can influence how susceptible you are to Shigellainfection. Variations in your genes can affect your immune response or how your body handles the bacteria’s attack, which might explain why you remained well while your friend got sick.
2. Can my genes make my shigellosis infection worse or longer?
Section titled “2. Can my genes make my shigellosis infection worse or longer?”Yes, they can. Host genetic factors are known to significantly influence both your susceptibility to Shigellainfection and the severity of the disease. Variations in your genes can affect how intensely your immune system responds to the bacteria, potentially leading to more severe symptoms or a longer recovery time for you compared to others.
3. Does my family’s background affect how likely I am to get shigellosis?
Section titled “3. Does my family’s background affect how likely I am to get shigellosis?”Your genetic background, which you share with your family, can certainly play a role. Research shows that host genetic factors influence an individual’s susceptibility to Shigellainfection. This means that certain genetic variations common in specific populations or families might make some individuals more or less prone to developing shigellosis.
4. Are babies in my family more at risk for shigellosis because of their genes?
Section titled “4. Are babies in my family more at risk for shigellosis because of their genes?”Yes, they might be. Studies specifically highlight host genetic factors that influence infant susceptibility to Shigella-associated diarrhea, especially within the first year of life. If certain genetic variations run in your family, they could predispose your infants to a higher risk of infection compared to other babies.
5. If shigellosis is common, why don’tall people get very sick from it?
Section titled “5. If shigellosis is common, why don’tall people get very sick from it?”Even with widespread exposure to Shigella, infection outcomes are highly varied. This heterogeneity is partly due to individual host genetic factors. Your genes influence how your immune system responds to the bacteria and how well your body can fight off the infection, leading to different levels of sickness among people.
6. Can good hygiene really protect me if shigellosis runs in my family?
Section titled “6. Can good hygiene really protect me if shigellosis runs in my family?”Absolutely, good hygiene is crucial and can significantly reduce your risk, even if you have a genetic predisposition. While host genetic factors play a role in susceptibility, environmental factors like sanitation and hygiene are vital. Maintaining excellent hygiene practices can help prevent exposure to the bacteria, thus mitigating any increased genetic risk you might have.
7. Could my child’s genes mean they have lasting problems from shigellosis?
Section titled “7. Could my child’s genes mean they have lasting problems from shigellosis?”It’s possible. While shigellosis can have severe long-term consequences like stunting and cognitive issues, host genetic factors can influence the severity of the initial disease. If your child has genetic variations that lead to a more severe infection, they might be at a greater risk for these adverse long-term effects.
8. Does my immune system’s response to shigella depend on my genes?
Section titled “8. Does my immune system’s response to shigella depend on my genes?”Yes, your immune system’s response to Shigellais indeed influenced by your genes. Host genetic factors, particularly those affecting the host immune response, are recognized for their role in determining susceptibility to infection. Variations in your genes can dictate how strongly or effectively your body’s immune cells react to the invading bacteria.
9. Would a genetic test tell me if I’m more prone to shigellosis?
Section titled “9. Would a genetic test tell me if I’m more prone to shigellosis?”In theory, yes, a genetic test could identify specific host genetic factors associated with susceptibility. While research has identified several genetic variants linked to shigellosis risk, these findings are still emerging and often specific to certain populations. Currently, such tests are primarily research tools rather than widely available clinical diagnostics.
10. Why do some people seem to recover from shigellosis faster than others?
Section titled “10. Why do some people seem to recover from shigellosis faster than others?”Individual differences in recovery time can be influenced by your genetic makeup. Host genetic variations play a role in determining the severity of the disease and how your body responds to the infection. These genetic factors can affect your immune system’s efficiency in clearing the bacteria and repairing tissue damage, leading to varied recovery rates.
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
Section titled “References”[1] Duchen, D, et al. “Host genome wide association study of infant susceptibility to Shigella-associated diarrhea.” Infect Immun, 2021.
[2] Khalil, I. A., et al. “Morbidity and Mortality Due to Shigella and Enterotoxigenic Escherichia coli Diarrhoea: The Global Burden of Disease Study 1990–2016.”Lancet Infect Dis, vol. 18, 2018, pp. 1229–1240.
[3] Schnee, A. E., et al. “Identification of Etiology-Specific Diarrhea Associated with Linear Growth Faltering in Bangladeshi Infants.”Am J Epidemiol, vol. 187, 2018, pp. 2210–2218.
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