Decreased Susceptibility To Bacterial Infection

Introduction

Decreased susceptibility to bacterial infection refers to an individual’s inherent or genetically influenced ability to resist infection by bacteria, or to experience less severe disease outcomes upon exposure. While environmental factors and pathogen virulence play significant roles, host genetics are increasingly recognized as critical determinants of an individual’s immune response and overall susceptibility. Understanding these genetic factors can shed light on the complex interplay between host and pathogen, revealing mechanisms of natural immunity.

Background

Variations in individual immune responses to bacterial pathogens are common, leading to diverse health outcomes ranging from asymptomatic carriage to severe, life-threatening disease. Studying individuals who exhibit decreased susceptibility provides valuable insights into protective immune mechanisms. A prominent example is the host response toMycobacterium tuberculosis(MTB), the causative agent of tuberculosis (TB), which remains a major global health challenge. Despite widespread exposure, only a fraction of exposed individuals develop active disease, and some appear to resist infection entirely. Research indicates a significant genetic component to this resistance, with studies demonstrating high heritability for the MTB infection resistance phenotype.^[1]

Biological Basis

Genetic variations within the human genome can modulate the immune system’s ability to detect, respond to, and clear bacterial pathogens. These variations can affect the expression or function of immune receptors, signaling molecules, and effector proteins, thereby influencing the strength and nature of the immune response. Genome-wide association studies (GWAS) have been instrumental in identifying specific genetic loci associated with resistance to bacterial infections. For instance, a locus at 10q26.2 has been identified as significantly associated with resistance to M. tuberculosisinfection across multiple populations.^[2] Variants within this region, such as rs77513326 , rs28703703 , and rs17155120 , are located in regulatory genomic regions characterized by active enhancer signatures in immune cells like T helper 17 (Th17) cells, memory T cells, natural killer cells, and CD8+ T cells.^[2] These protective variants have been linked to decreased expression of the nearby gene ADAM12 in monocytes.^[2] Lower ADAM12 expression may lead to increased production of Th17 cytokines, which are associated with a protective phenotype against M. tuberculosisinfection.^[2] Additionally, a locus on chromosome 5q31.1 has been associated with tuberculin skin test (TST) reactivity in HIV-positive individuals from TB-endemic regions.^[1] Other studies have linked genes like SLC6A3, SLC11A1, and regions on chromosomes 2 (q14, q21-q24) and 5 (p13-q22) to resistance to MTB infection.^[1] These findings highlight the complex genetic architecture underlying host resistance to bacterial pathogens.

Clinical Relevance

Understanding the genetic basis of decreased susceptibility to bacterial infection has profound clinical implications. Identifying individuals with protective genetic profiles could enable improved risk stratification, allowing for targeted preventative strategies or more personalized treatment approaches. For example, in the context of TB, genetic markers could help identify individuals at lower risk of infection or disease progression, or those who might benefit most from specific vaccination strategies. Furthermore, insights into the functional consequences of protective genetic variants, such as the role ofADAM12 in Th17 cell function, can uncover novel therapeutic targets for enhancing host immunity or developing new antimicrobial agents. Diagnostic tools like the Tuberculin Skin Test (TST) and Interferon-gamma Release Assays (IGRAs) are used to assess M. tuberculosisinfection status, and genetic insights can help interpret these results in diverse populations.^[1]

Social Importance

The social importance of understanding decreased susceptibility to bacterial infection extends to public health and global disease control. By identifying populations or individuals with natural resistance, public health initiatives can be tailored to focus resources where they are most needed. This knowledge contributes to a deeper understanding of population-level immunity, informing strategies for vaccine development and implementation, and potentially reducing the overall burden of infectious diseases. For diseases like tuberculosis, which disproportionately affect vulnerable populations, deciphering the genetics of resistance can inform equitable health policies and contribute to achieving global disease eradication goals.

Methodological and Phenotypic Definition Constraints

Research into decreased susceptibility to bacterial infection, as exemplified by studies onMycobacterium tuberculosisinfection, often faces inherent methodological limitations that can impact the interpretation of genetic associations. The sample sizes in individual cohorts, even when combined in meta-analyses, can be modest, potentially affecting statistical power and the precise estimation of effect sizes, despite efforts to identify significant associations.^[2]Furthermore, the definition of complex phenotypes like “resistance” or “susceptibility” to infection can introduce heterogeneity; for instance, classifying individuals with active pulmonary tuberculosis into an “infected” group alongside those with latent infection, though justified for increasing power, might not fully capture the nuanced spectrum of host responses to bacterial exposure.^[2]The reliance on immunological assays such as the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) to define infection status presents additional challenges. While IGRAs offer improved specificity by avoiding cross-reactivity with BCG vaccination, TST results can be confounded by prior immunization, and both assays may yield false negatives in immunocompromised individuals due to anergy.^[1]Such diagnostic limitations can lead to misclassification of true infection status, potentially diluting or distorting observed genetic effects and complicating the identification of robust genetic determinants for susceptibility to bacterial infections. In some analyses, genetic associations might also be conducted without full adjustment for all potential covariates, which could leave room for residual confounding by unmeasured factors.^[2]

Generalizability Across Diverse Populations

A significant challenge in understanding genetic susceptibility to bacterial infections lies in ensuring the generalizability of findings across ethnically diverse populations. While studies may include cohorts from various ancestries, observed genetic associations, allele frequencies, and linkage disequilibrium (LD) patterns can vary considerably.^[2] For example, allele frequencies for key variants might differ between a study cohort and broader 1000 Genomes reference populations, and LD blocks can exhibit weaker structures in some replication cohorts compared to discovery cohorts, indicating population-specific genetic architectures that influence the transferability of results.^[2] These discrepancies highlight the need for extensive replication in a multitude of ancestral groups and careful consideration of population structure, even when adjusting for principal components in analyses.^[1]The “specific ethnic origin” of certain cohorts, while offering valuable insights into under-represented populations, also underscores that findings from one group may not be directly applicable to others without further validation, thereby limiting the universal applicability of identified genetic loci for general bacterial infection susceptibility.^[2]

Unaccounted Environmental and Biological Complexity

The genetic landscape of susceptibility to bacterial infection is highly intricate, often influenced by a myriad of environmental factors and complex biological interactions that are difficult to fully account for in genetic association studies. While some studies investigate and adjust for known covariates, an unadjusted genetic association analysis, even after finding “no significant association” with measured covariates, may still be susceptible to confounding from unmeasured environmental variables.^[2]Factors such as exposure intensity, nutritional status, co-infections, or other lifestyle components can significantly modulate an individual’s immune response and infection outcome, acting as powerful confounders or modifiers of genetic effects.

Furthermore, a genome-wide association study primarily identifies statistical associations, which represent only one piece of a larger biological puzzle. While functional annotations and eQTL analyses can suggest potential mechanisms, such as the involvement of ADAM12expression and Th17 cytokine production inM. tuberculosis resistance.^[2] the complete elucidation of causal pathways, gene-environment interactions, and the full spectrum of genetic variants contributing to the “missing heritability” of complex traits remains an ongoing challenge. This complexity means that identified loci, while significant, likely represent only a fraction of the genetic architecture governing resistance to bacterial infections.

Variants

Several genetic variants and their associated genes play a role in modulating an individual’s susceptibility to bacterial infections, particularly Mycobacterium tuberculosis(MTB). These variants can influence fundamental cellular processes, immune responses, and disease progression. Understanding these genetic associations can shed light on the mechanisms of natural resistance and inform public health strategies in regions where infections like tuberculosis are highly prevalent.

The gene C10orf90, also known as FATS (Fragile-site Associated Tumor Suppressor), is a tumor suppressor gene located on chromosome 10q26.2, which is involved in promoting p53 activation in response to DNA damage, a critical pathway for cellular integrity and immune regulation. Variants within or near C10orf90 have been linked to resistance against M. tuberculosisinfection, with the most significant signal observed atrs17155120 .^[2] The minor T allele of rs17155120 is associated with a protective effect, conferring decreased odds of M. tuberculosisinfection.^[2] This variant, along with others in high linkage disequilibrium like rs56106518 , maps to intronic and upstream regions of C10orf90 and is associated with decreased expression of the nearby gene ADAM12 in monocytes, further contributing to a protective effect against M. tuberculosis.

Another significant locus is found on chromosome 5q31.1, involving the gene SLC25A48 and its variant rs877356 . SLC25A48 encodes a mitochondrial transporter protein, a member of the solute carrier family 25, which are vital for regulating the exchange of metabolites across the mitochondrial inner membrane, impacting cellular metabolism and energy production.^[3] Variants in this region, including rs877356 , have shown a genome-wide significant association with tuberculin skin test (TST) reactivity, a measure of immune response to M. tuberculosisinfection, particularly in HIV-positive individuals from tuberculosis hyper-endemic regions.^[1] The association of rs877356 with TST induration status suggests its role in modulating the host immune response to bacterial antigens, thereby influencing susceptibility or resistance to infection.

Other genetic factors contribute to the complex landscape of host defense. The ZFYVE1 gene, with its variant rs2333021 , is involved in endosomal trafficking and autophagy, essential cellular processes for degrading pathogens and presenting antigens to the immune system. Similarly, ESR1, encoding Estrogen Receptor 1, plays a role in immune modulation, where estrogen signaling can influence inflammatory responses and host defense against various pathogens, withrs1293940 potentially altering receptor activity. FRY (rs2520696 ) contributes to cell signaling and cytoskeletal dynamics, crucial for immune cell migration and pathogen recognition, while the LINC02881 - CXCL12 locus, including rs7082209 , impacts the expression of CXCL12, a chemokine critical for immune cell recruitment to sites of infection. Finally, theU3 - MGC4859 locus, with rs7808481 , may influence ribosome biogenesis, affecting the overall functionality and development of immune cells. These diverse genetic elements underscore the multifaceted nature of host immunity and its impact on susceptibility to bacterial infections.^{[1], [2]}

Key Variants

RS ID	Gene	Related Traits
rs2333021	ZFYVE1	decreased susceptibility to bacterial infection severe acute respiratory syndrome, COVID-19
rs1293940	ESR1	decreased susceptibility to bacterial infection bone tissue density
rs877356	SLC25A48	decreased susceptibility to bacterial infection
rs2520696	FRY	decreased susceptibility to bacterial infection
rs17155120 rs56106518	C10orf90	decreased susceptibility to bacterial infection
rs7082209	LINC02881 - CXCL12	decreased susceptibility to bacterial infection
rs7808481	U3 - MGC4859	decreased susceptibility to bacterial infection

Defining Decreased Susceptibility to Mycobacterium tuberculosisInfection

Decreased susceptibility to bacterial infection, specifically in the context ofMycobacterium tuberculosis(MTB), refers to an individual’s inherent resistance to establishing an infection following exposure to the pathogen. This trait is often termed “resistance to M. tuberculosis infection”.^[2]or the “MTB infection resistance phenotype”.^[1]While exposure to MTB is widespread in hyper-endemic regions, a notable proportion, estimated between 10-20%, of exposed individuals do not develop infection, suggesting a biological basis for this resistance.^[1]This conceptual framework distinguishes individuals who remain uninfected despite repeated exposure from those who develop latent MTB infection or progress to active tuberculosis disease, representing a spectrum of host-pathogen interactions.^[1]The precise definition of an uninfected state is critical for research and clinical practice, particularly in differentiating it from immune anergy or a successfully cleared infection. Heritability studies have supported the existence of a genetic component to this MTB infection resistance phenotype, highlighting the importance of identifying underlying biological mechanisms.^[1]Understanding this resistance is distinct from the progression of an established infection to active disease, which is influenced by factors like immunosuppression, such as that caused by HIV.^[1]

Diagnostic and Operational Criteria for Infection Status

The operational definition of Mycobacterium tuberculosisinfection status relies primarily on a combination of immunodiagnostic tests: the Tuberculin Skin Test (TST) and Interferon-Gamma Release Assays (IGRAs).^[2] The TST measures the induration resulting from a delayed-type hypersensitivity reaction to an intradermal injection of Mycobacterium tuberculosispurified protein derivative (PPD), with an induration of 5mm or greater, measured 48 to 72 hours post-injection, typically indicating infection in endemic areas.^[1] Conversely, a TST induration less than 5mm is generally considered negative.^[2] IGRAs, such as the QuantiFERON-TB Gold In-Tube (QFT-GIT), detect the concentration of IFN-γ produced in response to MTB-specific antigens, offering a more specific test as its antigens do not overlap with the Bacille Calmette-Guérin (BCG) vaccine.^[1] For research purposes, particularly in genome-wide association studies, precise diagnostic criteria are established to classify subjects as “uninfected” or “infected.” Uninfected subjects are typically defined by both a negative TST (< 5mm induration) and a negative IGRA result, often characterized by a null IFN-γ production.^[2] Conversely, infected subjects present with both a positive TST (≥ 5mm induration) and a positive IGRA, with specific IFN-γ production thresholds varying by study context (e.g., > 20.9 pg/mL or > 175 pg/mL).^[2]These combined criteria aim to provide a robust operational definition for the binary infection phenotype, minimizing misclassification and enabling genetic association analyses.

Classification and Confounding Factors in Infection Assessment

The classification of individuals regarding Mycobacterium tuberculosisinfection status is predominantly categorical, dividing subjects into “uninfected” versus “infected” groups based on the combined TST and IGRA results.^[2]However, the TST itself can be analyzed as a continuous variable (induration size) or a binary variable (positive/negative based on a ≥ 5mm threshold), reflecting both dimensional and categorical approaches to its measurement.^[1] This dual approach allows for flexibility in genetic modeling, such as using linear regression for continuous data or logistic regression for binary outcomes.^[1] Despite these standardized approaches, several confounding factors can complicate accurate classification. Immune anergy, particularly in immunosuppressed individuals such as those with HIV, can lead to false-negative TST and IGRA results, where an infected person fails to mount a detectable immune response.^[1] Researchers often mitigate this by excluding individuals suspected of anergy or by adjusting analyses for relevant covariates.^[1] Additionally, prior BCG vaccination can cause false-positive TST results due to antigenic overlap with PPD, although this effect typically diminishes over time and is not a concern with IGRAs.^[1]These factors highlight the need for careful consideration and methodological adjustments when defining and classifying infection status in diverse populations.

Genetic Predisposition to Bacterial Resistance

Decreased susceptibility to bacterial infection, particularlyMycobacterium tuberculosis (MTB), is significantly influenced by an individual’s genetic makeup, with studies showing high heritability for resistance phenotypes.^[1]Multiple inherited genetic variants contribute to this resistance, often through polygenic mechanisms involving several genes. For instance, genome-wide association studies (GWAS) have identified a significant locus at 10q26.2 associated with resistance to MTB infection in diverse populations.^[2] Specific variants within this region, such as rs17155120 , have been linked to a protective effect, where the minor allele T correlates with a lower proportion of infected individuals.^[2] Further genetic determinants include an association with the SLC11A1 gene, as well as candidate regions on chromosomes 2 (q14, q21-q24) and 5 (p13-q22).^[1] A locus on chromosome 5q31.1, encompassing SLC25A48/IL9, has also been associated with tuberculin skin test reactivity, a proxy for MTB infection status.^[1] Moreover, gene-gene interactions, such as specific haplotypes involving rs877356 and rs2069885 in the SLC25A48/IL9region, demonstrate a collective influence on infection resistance.^[1] These findings highlight a complex genetic architecture where various genes and their interactions contribute to an individual’s innate ability to resist bacterial pathogens.

Epigenetic Regulation and Gene Expression

Epigenetic mechanisms play a crucial role in modulating an individual’s immune response and, consequently, their susceptibility to bacterial infections. Genetic variants located within regulatory genomic regions can influence gene expression through epigenetic modifications, thereby affecting an individual’s resistance. For example, the variant rs77513326 , found within the 10q26.2 locus, is situated in a region characterized by specific histone marks, H3K4me1 and H3K27ac, which are indicative of active enhancers in T helper 17 (Th17) lymphocytes.^[2] This suggests that the variant may influence gene regulation by altering chromatin accessibility in critical immune cells.

The rs77513326 variant also overlaps ATAC (Assay for Transposase-Accessible Chromatin) peaks in various immune cells, including Th17 cells, memory T cells, natural killer cells, and CD8+ T cells.^[2] This indicates that these regions are actively accessible for transcription, further supporting their regulatory role. Expression quantitative trait loci (eQTL) analyses have linked variants like rs28703703 and rs17155120 to the expression of the nearby gene ADAM12.^[2] Specifically, the minor allele of these variants is associated with decreased ADAM12expression in monocytes, which confers a protective effect against MTB infection.^[2] These epigenetic and gene regulatory mechanisms fine-tune immune responses, contributing to decreased susceptibility to bacterial pathogens.

Environmental Influences and Comorbidities

Environmental factors and co-existing health conditions significantly shape an individual’s susceptibility to bacterial infections. Exposure levels to pathogens are a primary environmental determinant; for instance, studies on resistance to MTB infection often focus on individuals after intense exposure, highlighting the interplay between environmental challenge and innate immunity.^[2]Geographic location also plays a role, with studies conducted in tuberculosis hyper-endemic regions in East Africa and across distinct populations in Vietnam, France, and South Africa, suggesting that regional factors may influence infection patterns and resistance.^[1]Furthermore, an individual’s health status, including comorbidities, can profoundly impact their immune competence. For example, human immunodeficiency virus (HIV) infection is a significant comorbidity that alters immune function, making HIV-positive individuals more susceptible to various infections, including MTB.^[1]Research indicates that genetic loci influencing resistance to bacterial infection can have different associations or effects in immunocompromised populations, underscoring the complex gene-environment interactions that determine overall susceptibility.

Biological Background: Decreased Susceptibility to Bacterial Infection

Resistance to bacterial infections, particularly those caused by widespread pathogens like Mycobacterium tuberculosis(MTB), is a complex biological trait influenced by a combination of genetic, immunological, and environmental factors. Understanding the mechanisms underlying decreased susceptibility provides critical insights into host defense strategies and potential therapeutic targets. This trait often manifests as an individual’s ability to clear an infection, prevent its establishment, or limit its progression to active disease, even after significant exposure.^[1]

Genetic Predisposition to Resistance

The ability of an individual to resist bacterial infection, such as that byMycobacterium tuberculosis, has a significant genetic component, with studies demonstrating high heritability for infection resistance phenotypes among siblings.^[1]Genetic analyses have identified several loci associated with resistance to MTB infection. For instance, family-based linkage studies have implicated genes likeSLC6A3and a specific region on chromosome 11 (p14) in the infection outcome.^[1] Furthermore, a genome-wide microsatellite scan comparing individuals who remained persistently negative for MTB to those with latent infections revealed associations with the SLC11A1 gene and candidate regions on chromosomes 2 (q14, q21-q24) and 5 (p13-q22).^[1] Recent genome-wide association studies (GWAS) have further pinpointed specific genomic regions. A locus on chromosome 5q31.1 was found to associate with tuberculin skin test (TST) reactivity, a marker of MTB exposure and immune response, particularly in HIV-positive individuals.^[1] Within this region, variants like rs17062122 , rs10998959 , and rs11736841 near Loc100129281 and SLC25A48 were identified, with a haplotype including rs11736841 and a missense mutation in IL9 showing a strong association with negative TST results.^[1] Another significant locus at 10q26.2 has been identified across multiple populations, with variants such as rs77513326 , rs28703703 , and rs17155120 being consistently linked to resistance to MTB infection.^[2] These genetic findings highlight the polygenic nature of host susceptibility and resistance to bacterial pathogens.

Epigenetic Regulation and Gene Expression Modulators

Beyond the mere presence of genetic variants, the regulation of gene expression plays a crucial role in determining an individual’s susceptibility or resistance to bacterial infections. The genetic variants associated with resistance often reside in regulatory regions of the genome, influencing how genes are turned on or off in response to infection. For example, the variants at the 10q26.2 locus, includingrs77513326 , are situated in a regulatory genomic region characterized by specific epigenetic marks, such as H3K4me1 and H3K27ac histone modifications, which are indicators of active enhancer elements.^[2] This region displays an active enhancer signature particularly in T helper 17 (Th17) cells, suggesting its importance in immune cell function.^[2] Furthermore, chromatin accessibility assays (ATAC-seq) revealed that rs77513326 overlaps with accessible chromatin regions (ATAC peaks) in various immune cell types, including Th17 cells, memory T cells, natural killer (NK) cells, and CD8+ T cells.^[2] This indicates that these variants may influence the binding of transcription factors, thereby modulating gene expression. Indeed, expression quantitative trait loci (eQTL) analyses have linked these variants to the expression levels of the nearby gene ADAM12. Specifically, the minor alleles of rs28703703 and rs17155120 were associated with decreased expression of ADAM12 in monocytes, an effect that correlated with a protective outcome against M. tuberculosisinfection.^[2] This demonstrates a direct molecular pathway where genetic variation leads to altered gene expression, ultimately impacting host defense.

Cellular Immunity and Cytokine Signaling

The immune system’s ability to mount an effective response is central to decreased susceptibility to bacterial infection, with specific cell types and signaling pathways playing critical roles.ADAM12, a gene whose expression is modulated by protective genetic variants, encodes a matrix metalloprotease involved in a wide array of biological processes, including immune responses.^[2] Its expression has been noted in Th17 cells, which are a subset of T helper cells crucial for host defense against extracellular bacteria and fungi.^[2] Notably, studies have shown that knockdown of ADAM12 in human T cells leads to an increase in the production of key Th17 cytokines, including IL-17A, IL-17F, and IL-22.^[2]This increase in Th17 cytokine production is a significant mechanism for enhanced resistance. Higher levels of Th17 cytokines have been observed in individuals who test negative for MTB infection (TST-negative or persistent negative IGRA individuals) compared to those who are infected or convert to positive.^[2] Therefore, the protective effect of lower ADAM12 expression, as mediated by specific genetic variants, is likely achieved through the upregulation of these critical Th17-associated immune mediators, strengthening the host’s ability to combat M. tuberculosis. Additionally, IL9, a gene located near a protective locus on chromosome 5, produces a product associated with bronchial hyperresponsiveness, suggesting a role in inflammatory responses that could contribute to protection against M. tuberculosisinfection.^[1]

Host-Pathogen Interaction and Disease Pathophysiology

Mycobacterium tuberculosisinfection represents a major global health challenge, with a significant portion of the world’s population infected and a substantial number progressing to active tuberculosis disease.^[1]Decreased susceptibility to MTB infection refers to the host’s inherent ability to prevent the establishment or progression of the infection. This can involve diverse mechanisms, such as efficient mechanical clearance of inhaled bacteria, rapid eradication before immune memory is established, or effective localization of the infection without inducing a systemic response.^[1] The tuberculin skin test (TST) is a common diagnostic tool that measures a delayed-type hypersensitivity response to MTB antigens, indicating prior exposure and immune sensitization.^[1] However, interpreting TST results can be complex, as individuals can remain TST-negative despite exposure due to factors like anergy, where host immunosuppression or an inability to mount a proper delayed-type hypersensitivity response prevents a positive test.^[1] This is particularly relevant in vulnerable populations, such as HIV-positive individuals, where compromised T cell counts or activity can mask exposure.^[1] The correlation of ADAM12 expression with lung inflammation, where it is overexpressed in cells from asthmatic sputum and airway epithelium during allergic inflammatory reactions, further highlights its potential role in tissue-specific immune responses relevant to a lung pathogen like M. tuberculosis.^[2] Understanding these complex host-pathogen interactions and the physiological manifestations of resistance is crucial for developing effective prevention and treatment strategies.

Immune Cell Signaling and Cytokine Regulation

Decreased susceptibility to bacterial infection, particularlyMycobacterium tuberculosis, involves intricate immune signaling pathways, notably those governing T helper 17 (Th17) cell responses. Genetic variants, such as the G allele of rs28703703 , are associated with lower expression of ADAM12.^[2] This reduction in ADAM12, a matrix metalloprotease, leads to an increased production of Th17 cytokines, including IL-17A, IL-17F, and IL-22.^[2] Higher levels of these cytokines have been observed in individuals with natural resistance to M. tuberculosisinfection, suggesting a protective role against early stages of the pathogen.^[2] Another critical signaling pathway involves IL9 and its downstream effects on immune and structural cells. A locus at 5q31.1, featuring the IL9 gene, is associated with tuberculin skin test reactivity.^[1] IL9 directly stimulates mucin transcription in respiratory epithelial cells and induces CCL11expression via STAT3 signaling in human airway smooth muscle cells.^[1]This activation of STAT3 signaling contributes to eosinophil chemotaxis and broader airway inflammation, which may paradoxically contribute to reduced risk ofM. tuberculosisinfection by altering the local microenvironment.^[1]

Cellular Defense Mechanisms and Apoptosis

Host defense against bacterial infections, such as M. tuberculosis, relies on robust cellular mechanisms like autophagy and apoptosis, tightly regulated by specific proteins and pathways. The gene C10orf90, located near the ADAM12 locus, encodes an E3 ubiquitin ligase that plays a role in stabilizing the p53 transcription factor and promoting its activation in response to DNA damage.^[2] E3 ubiquitin ligases are known to be involved in the defense against M. tuberculosis, particularly through the induction of autophagy, a process critical for clearing intracellular pathogens.^[2] The p53 transcription factor acts as a master regulator of both autophagy and apoptosis, both of which are key processes for host cells to limit pathogen spread.^[2] Recent research indicates that p53-induced apoptosis is critical for inhibiting mycobacterial survival and enhancing macrophage resistance, a mechanism that may be partially mediated by IL-17.^[2] This highlights a systems-level integration where genetic predispositions influence crucial cellular defense pathways to enhance resistance.

Airway and Tissue Remodeling Pathways

The local tissue environment, particularly in the airways, significantly influences susceptibility to respiratory infections. ADAM12, a matrix metalloprotease whose expression is inversely correlated with resistance to M. tuberculosis, is linked to a broad range of biological processes including tissue remodeling and inflammation.^[2] ADAM12 expression is notably elevated in conditions of lung inflammation, such as asthmatic sputum and allergic airway inflammatory reactions.^[2] Lowering ADAM12 expression, as seen with the protective G allele of rs28703703 , may modulate the extracellular matrix and inflammatory milieu, thereby influencing pathogen containment or clearance.^[2] Similarly, IL9plays a role in airway remodeling processes that may contribute to altered infection susceptibility. Beyond its direct effects on mucin production,IL9 stimulates IL13 in airway epithelial cells, further exacerbating airway inflammation.^[1] While increased inflammation might seem detrimental, these IL9-mediated changes, including increased mucous production and the recruitment of eosinophils via CCL11, could create an environment less conducive for M. tuberculosis survival or dissemination within the respiratory tract.^[1]

Genetic Regulatory Elements and Gene Expression Control

Genetic predisposition to bacterial infection resistance is often mediated by variants located within regulatory genomic regions that influence gene expression. Several variants associated with decreased susceptibility toM. tuberculosisinfection, includingrs28703703 and rs77513326 , are situated in regions characterized by specific histone marks like H3K4me1 and H3K27ac, indicative of active enhancer signatures, particularly in Th17 lymphocytes.^[2] These regulatory elements, which also overlap ATAC peaks in various immune cells, including Th17, memory T, NK, and CD8+ T cells, orchestrate the precise control of gene transcription.^[2] The variant rs28703703 acts as a cis-eQTL for ADAM12 in monocytes, where the protective G allele is associated with decreased ADAM12 expression.^[2]This demonstrates a direct link between genetic variation in regulatory regions and altered gene dosage, which subsequently impacts immune responses. Such fine-tuned transcriptional regulation, through the interplay of genetic variants and chromatin accessibility, ultimately shapes the immune cell phenotype and functional capacity, contributing to a host’s natural resistance to infection.^[2]

Adaptive Evolution of Host Resistance

The identification of genetic loci, such as the one at 10q26.2, that confer decreased susceptibility to Mycobacterium tuberculosisinfection strongly suggests a history of adaptive evolution driven by natural selection. Variants likers17155120 , rs77513326 , and rs28703703 are located in a regulatory genomic region and are associated with a significant protective effect, with the minor allele decreasing the expression of the nearby gene ADAM12 in monocytes.^[2] This modulation of ADAM12 expression likely enhances the host’s ability to resist M. tuberculosis, providing a clear fitness advantage in populations exposed to the pathogen. Such strong selective pressures would favor the increase in frequency of these protective alleles through a process of positive selection, potentially leading to selective sweeps in regions with historical high pathogen prevalence. The observation of high heritability for M. tuberculosisinfection resistance further underscores the significant role of genetic factors in this adaptive response.^[1]

Population Genetic Signatures and Dispersal

The presence of specific protective alleles, such as those at 10q26.2, across geographically distinct populations—including Vietnamese, French, and South African cohorts—highlights the complex interplay of population genetic forces in shaping human immune defenses. While independent adaptive events cannot be ruled out, the shared genetic basis for resistance suggests either ancient origins followed by dispersal through migration, or convergent evolution under similar selective pressures. Genetic drift, founder effects, or population bottlenecks in ancestral human populations could have influenced the initial frequencies of these alleles, which were then subjected to differential selective pressures as human populations expanded and encountered M. tuberculosis across diverse environments. Linkage disequilibrium patterns observed around these protective variants, when compared to 1000 Genomes populations, provide valuable insights into the historical trajectories and demographic influences on their current distribution.^[2]

Co-evolutionary Dynamics and Functional Trade-offs

The persistent threat of M. tuberculosis throughout human history has likely driven a continuous co-evolutionary arms race between the pathogen and its human host. The identified regulatory variants affecting ADAM12expression exemplify how subtle genetic changes can lead to pleiotropic effects, where a single locus influences multiple cellular pathways to confer a protective phenotype against infection. While conferring a clear advantage in pathogen resistance, such adaptations can also involve evolutionary trade-offs; the alteredADAM12 expression, while beneficial against M. tuberculosis, might have other, as yet unknown, implications for immune function or overall health. Understanding these potential evolutionary constraints and the adaptive significance of such loci is crucial for a comprehensive view of human immune system evolution and for developing novel strategies against infectious diseases.

Frequently Asked Questions About Decreased Susceptibility To Bacterial Infection

These questions address the most important and specific aspects of decreased susceptibility to bacterial infection based on current genetic research.

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1. Why do some people never get sick, even after exposure?

It’s often due to your unique genetic makeup. Variations in your genes can give your immune system a natural advantage, helping it detect and fight off bacteria more effectively before you even feel sick. This inherent resistance means your body might clear the pathogen quickly, leading to no symptoms or a very mild response.

2. My family always catches things; will I too?

There’s a significant genetic component to how susceptible you are to infections, so if your family has a history of getting sick easily, you might share some of those genetic predispositions. However, genetics aren’t the whole story; environmental factors and exposure also play a big role. Your individual immune response can still differ from your family members.

3. If exposed to bacteria, why might I not get infected?

Your genes can give you a natural ability to resist infection. Genetic variations affect how your immune system’s receptors and signaling molecules work, allowing your body to quickly recognize and clear bacterial pathogens. For instance, some people have genetic variants that enhance protective immune responses, like increased production of certain immune cytokines.

4. Does my ancestry affect my natural infection resistance?

Yes, your genetic ancestry can influence your natural resistance to bacterial infections. Different populations can have varying frequencies of protective genetic variants and unique patterns in their DNA. This means that genetic associations found in one population might not be the same in another, highlighting the importance of diverse research.

5. Why do some get severe infections, others mild ones?

This difference often comes down to your genetics, which shape your immune response. Genetic variations can influence the strength and nature of your immune system’s ability to fight off bacteria. For example, some people have genetic profiles that lead to a more effective or protective immune reaction, minimizing disease severity.

6. Could a DNA test show my infection resistance?

In the future, genetic testing might offer insights into your susceptibility or resistance to certain bacterial infections. Researchers are identifying specific genetic markers associated with resistance, like those linked to tuberculosis. This information could eventually help predict your risk or guide personalized preventative strategies, though it’s not a common diagnostic tool for this purpose yet.

7. Why might I be exposed to TB but not get sick?

Many people exposed to Mycobacterium tuberculosisdon’t develop active disease, and this is largely influenced by your genetics. Your immune system might have protective genetic variations that allow it to effectively resist infection or contain the bacteria. For example, specific gene variations like those affectingADAM12expression can lead to immune responses that prevent the disease from progressing.

8. Why might my infection test results be interpreted differently?

The interpretation of tests like the Tuberculin Skin Test (TST) or Interferon-gamma Release Assays (IGRAs) can be complex and might vary based on your background. Factors like previous vaccinations, your immune status, or your specific population’s genetic profile can influence these results. Genetic insights are crucial to accurately interpret these tests, especially in diverse groups.

9. Am I just born with better immunity to some bacteria?

Yes, some individuals are inherently or genetically predisposed to have better immunity against certain bacterial infections. Variations in your genes can lead to a more robust immune system, allowing it to respond more effectively to pathogens. This natural advantage can mean you’re less likely to get infected or experience severe symptoms compared to others.

10. Can doctors use my genetics to treat my infections better?

Understanding your genetic profile could lead to more personalized and effective treatment for bacterial infections in the future. Knowing your genetic susceptibility or resistance can help doctors tailor preventative strategies or choose specific treatments that align with your unique immune response. For instance, insights from genetics can uncover new therapeutic targets to enhance your immunity.

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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] Sobota RS, et al. “A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa.”PLoS Genet, 2017.

[2] Quistrebert J, et al. “Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations.”PLoS Genet, 2021.

[3] Palmieri F. “The mitochondrial transporter family SLC25: identification, properties and physiopathology.” Molecular aspects of medicine, 2013.