Bartonella Seropositivity
Introduction
Background of Bartonella Infection
Bartonella is a diverse genus of bacteria, with several species known to cause a range of diseases in humans, often transmitted through arthropod vectors like fleas, ticks, and lice. Common manifestations include cat scratch disease (Bartonella henselae), trench fever (Bartonella quintana), and Carrion's disease (Bartonella bacilliformis), among others. Seropositivity to Bartonella indicates the presence of specific antibodies against Bartonella antigens in an individual's blood, signifying a past or current exposure to the bacterium and the host's immune response. [1] These antibodies are detected through serological tests, which serve as a marker for epidemiological surveillance and individual diagnostic assessment. [1]
Biological Basis of Seropositivity
The detection of Bartonella antibodies is a key indicator of an adaptive immune response. When an individual is exposed to Bartonella, their immune system produces antibodies that specifically bind to bacterial components. [1] Serological assays, such as fluorescent bead-based multiplex serology, measure the levels of these antibodies, often quantified as median fluorescence intensity (MFI) . [1], [2] A person is generally classified as seropositive if their antibody levels exceed a predefined threshold. [1] It is recognized that serological tests can sometimes exhibit low-level cross-binding with non-specific antibodies, which may not always reflect a true infection. [1] Genetic factors play a significant role in modulating an individual's immune response to infectious agents. Genome-wide association studies (GWAS) and HLA association studies are utilized to identify genetic variants, including single nucleotide polymorphisms (SNPs), that are linked to susceptibility to infection or the variability in antibody-mediated immune responses within exposed populations . [1], [3], [4] These studies investigate both the binary serostatus (seropositive vs. seronegative) and the quantitative antibody levels. [1]
Clinical Relevance
The clinical relevance of Bartonella seropositivity lies in its utility for diagnosing Bartonella infections, which can present with a wide spectrum of symptoms, ranging from asymptomatic to severe systemic illness. Identifying genetic determinants associated with seropositivity can elucidate why some individuals are more susceptible to infection or why their immune responses vary, potentially influencing disease progression and severity. [1] Such genetic insights could help identify individuals at higher risk for Bartonella disease or those who may exhibit a suboptimal immune response, even after exposure. Enhancing the specificity of serological tests by conducting future studies in individuals with a clear history of exposure (or lack thereof) is crucial for uncovering clinically significant genetic associations. [1]
Social Importance
From a societal perspective, understanding Bartonella seropositivity and its genetic influences contributes to broader public health initiatives and infectious disease epidemiology. Genetic research in this area can provide insights into population-level susceptibility and immune resilience, informing strategies for disease prevention and control. [1] Given that environmental factors are also significant non-heritable determinants of infectious diseases, integrating environmental data with genetic studies is essential for a comprehensive understanding of disease patterns. [1] The dynamic nature of antibody levels, influenced by various host and environmental factors, underscores the complexity of assessing immune responses over time. [1] Ultimately, this research can lead to improved diagnostic tools, more targeted public health interventions, and a better understanding of how human genetic variation shapes our interaction with Bartonella species.
Methodological and Statistical Constraints
The analysis of bartonella seropositivity, while leveraging a large UK Biobank dataset, encountered several methodological and statistical limitations. Although genome-wide genotyping data were available for a vast cohort of 488,000 participants, the specific serological analyses were conducted on a smaller subsample of approximately 9,724 individuals, further restricted to 8,761 White British participants for certain analyses. [1] This reduction in sample size, particularly for specific pathogens, can limit statistical power and introduce challenges in the clinical interpretation of findings, as previous research indicates that many infectious disease GWAS have been hampered by small sample sizes. [1] The exclusion of analyses with fewer than 50 cases due to concerns about unstable statistics further highlights the sensitivity of these studies to sample size constraints. [5]
Furthermore, the study addressed potential statistical issues such as heavily skewed data and inflation of variance in antibody MFI measurements by employing a logarithmic transform, acknowledging the risk of violating linear regression assumptions. [1] Despite these careful statistical adjustments, the broader landscape of human infectious disease GWAS is characterized by diverse methodologies across studies, which complicates direct comparisons and replication efforts. [1] While a similar preprint using the same UK Biobank data found comparable associations, this also underscores the ongoing need for standardized and robust analytical approaches to confirm the reliability of identified genetic variants. [1]
Generalizability and Phenotypic Measurement Limitations
A significant limitation affecting the generalizability of the findings is the restriction of the study population to individuals of White British ancestry, identified through principal component analysis. [1] This methodological choice was made to mitigate bias from population stratification, a known confounder in genetic association studies. [1] However, this focus inherently limits the direct applicability of the results to other populations, as genetic predispositions and immune response mechanisms, including the prevalence and impact of specific HLA alleles, can differ considerably across diverse ancestral backgrounds. [1] Future research should prioritize multi-ancestry studies to broaden the understanding of these genetic determinants.
The study's reliance on antibody-mediated immune responses and predefined seropositivity thresholds as phenotypic markers of infection also presents inherent limitations. [1] While the serological methods, including fluorescent bead-based multiplex technology and Median Fluorescence Intensity (MFI) quantification, were validated, such tests carry intrinsic diagnostic constraints, notably the potential for low-level cross-binding by non-specific antibodies. [1] To enhance the specificity and clinical significance of genetic associations, ideally, future serological investigations would include participants with well-documented histories of exposure or non-exposure to the infectious agent, thereby refining the phenotypic definition. [1]
Unaccounted Environmental and Gene-Environment Interactions
The research acknowledges that unmeasured environmental or socioeconomic confounders could have influenced the observed results. [1] Although the study controlled for a range of covariates, including sex, age, UK Biobank assessment center, and the first 20 principal components. [1] The omission of specific environmental data in the analytical model represents a knowledge gap, suggesting that a more comprehensive understanding of disease susceptibility and immune response requires future genetic studies to integrate environmental factors more explicitly into their design. [1]
Furthermore, despite the identification of genetic determinants of antibody responses, the precise underlying pathophysiology linking infectious agents to various health outcomes often remains incompletely understood, and their true causal effects are frequently unclear. [1] This highlights that genetic factors, while important, represent only one component within a complex web of influences governing infectious disease susceptibility and immune function. A more holistic understanding necessitates not only continued genetic discovery but also a deeper exploration of how these genetic predispositions interact with environmental exposures and other biological pathways, an area that warrants significant future investigation.
Variants
The _RNF13_ (Ring Finger Protein 13) and _ANKUB1_ genes play important roles in fundamental cellular processes that can influence immune system function. _RNF13_ encodes a protein involved in the ubiquitination pathway, a critical regulatory mechanism that tags proteins for degradation or modifies their activity, thereby impacting cellular signaling, stress responses, and the immune system's ability to respond to pathogens. _ANKUB1_, also known as Ankyrin Repeat Domain Containing 11 (_ANKRD11_), is a transcription coregulator involved in chromatin remodeling and gene expression, which means it can indirectly shape the development and function of immune cells by regulating the expression of various genes. Genetic variants, such as single nucleotide polymorphisms (SNPs), have been consistently shown to influence the host's antibody-mediated immune responses to infectious diseases . [1], [2]
The genetic variant *rs35336664* is a single nucleotide polymorphism that, depending on its location, could potentially alter the expression levels, protein structure, or splicing of _RNF13_ or _ANKUB1_, thereby affecting their biological functions. For _RNF13_, such an alteration might lead to dysregulated ubiquitination, impacting immune signaling pathways crucial for recognizing and responding to bacterial infections. Similarly, a variant in _ANKUB1_ could modify the intricate regulation of gene expression within immune cells, influencing their differentiation, activation, or ability to produce specific immune mediators. These genetic differences can lead to variations in antibody production and overall immune response, which are often reflected in seropositivity for various pathogens. [3] Genome-wide association studies have repeatedly identified genetic determinants of antibody levels and serostatus for a range of infectious agents. [1]
The implications of *rs35336664* for Bartonella seropositivity stem from the potential for altered _RNF13_ or _ANKUB1_ function to influence the immune system's interaction with the bacterium. For example, changes in ubiquitination (via _RNF13_) could affect the presentation of Bartonella antigens to immune cells, or altered gene expression (via _ANKUB1_) might modify the cellular environment, impacting the persistence of the bacteria or the host's ability to clear the infection. Such genetic influences could manifest as higher or lower Bartonella antibody titers, indicating differences in exposure, susceptibility, or immune clearance efficiency. Understanding these genetic predispositions is vital for identifying individuals who may be at an increased risk for certain infection outcomes or who may respond differently to pathogen exposure . [6], [7]
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs35336664 | RNF13, ANKUB1 | bartonella seropositivity |
Conceptual and Operational Definition
Bartonella seropositivity refers to the detection of specific antibodies against Bartonella species in an individual's blood serum, indicating a past or present immune response to the pathogen. Conceptually, it signifies prior exposure to the Bartonella bacterium, leading to the production of pathogen-specific antibodies by the immune system. [1] Operationally, an individual is defined as seropositive if their antibody levels surpass a predetermined "seropositivity threshold". [1] This threshold distinguishes between the presence and absence of a significant antibody response, categorizing individuals into "seropositive" or "seronegative" groups for research and clinical purposes. [1]
Diagnostic and Measurement Methodologies
The determination of Bartonella seropositivity relies on various immunological assays designed to quantify antibody levels. Common approaches include fluorescent bead-based multiplex serology technology, such as the Luminex 100 platform, which measures Median Fluorescence Intensity (MFI) as a standardized quantification of antibody amounts. [1] Additionally, commercially available Enzyme-Linked Immunosorbent Assays (ELISA) are widely used to detect specific IgG antibodies. [3] For these methods, precise diagnostic criteria are established, often involving specific cut-off values or thresholds; for instance, some definitions require positivity for a minimum number of target antigens or a comparison against a positive control value. [1] These thresholds are crucial for accurate classification and have often been validated against reference standards for various infectious agents. [1]
Classification Systems and Associated Terminology
Seropositivity for Bartonella can be classified using both categorical and dimensional approaches. The most straightforward classification is binary, where individuals are designated as either "seropositive" (cases) or "seronegative" (controls) based on whether their antibody levels exceed a defined threshold. [1] This "discrete serostatus" is fundamental for identifying genetic variants associated with previous infections. [1] Alternatively, a dimensional approach involves quantifying the actual antibody levels, often expressed as MFI or optical density values, which can be further categorized into semi-quantitative groups based on absorbance. [1] Key terminology associated with this field includes "antibody MFI," "seroprevalence" (the percentage of seropositive individuals in a population), and "pathogen burden," which can be inferred from the sum of seropositive reactions to multiple agents. [1]
The Humoral Immune Response and Serological Detection
Seropositivity for Bartonella indicates the presence of specific antibodies against this infectious agent in an individual's blood, serving as a biological marker of past or current exposure. [1] These antibodies are critical biomolecules, primarily immunoglobulins, produced by the adaptive immune system to recognize and neutralize foreign pathogens. Quantitative measurements, such as Median Fluorescence Intensity (MFI), provide a standardized assessment of the amount of antibody present, thereby reflecting the strength and magnitude of the humoral immune response. [1]
The detection of these specific antibodies is typically achieved through serological tests like fluorescent bead-based multiplex serology or Enzyme-Linked Immunosorbent Assays (ELISA). [1] These methods allow for the classification of individuals as seropositive or seronegative based on established thresholds. [1] While seropositivity generally signifies an immune response to infection, it is recognized that low-level cross-binding with other non-specific antibodies can occur, which may not always be representative of a direct infection. [1]
Genetic Architecture of Antibody Production
Genetic mechanisms significantly influence an individual's capacity to mount an antibody-mediated immune response. Genome-wide association studies (GWAS) identify specific genetic variants, such as single nucleotide polymorphisms (SNPs), that are statistically associated with variations in antibody levels or seropositivity status. [1] These genetic differences can impact various facets of immune function, from antigen recognition to the efficiency of antibody synthesis, thereby modulating the overall strength and persistence of the immune response.
A prominent genetic region influencing immune responses is the Major Histocompatibility Complex (MHC), located on chromosome 6, which harbors the highly polymorphic Human Leukocyte Antigen (HLA) genes. [1] HLA alleles encode proteins essential for presenting pathogen-derived peptides to T cells, a critical step in initiating adaptive immunity. Variations in these HLA alleles and their corresponding amino acid residues can profoundly affect the immune system's ability to recognize antigens and subsequently orchestrate an effective antibody response. [1] Heritability analyses further underscore the substantial contribution of genetic factors to the observed variability in antibody levels among individuals. [4]
Molecular and Cellular Regulation of Immunity
The generation of specific antibodies against pathogens like Bartonella involves intricate molecular and cellular pathways. Upon exposure, antigen-presenting cells (APCs) internalize and process pathogen antigens, then display them on their surface via HLA molecules. This presentation engages specific T helper cells, which in turn activate B lymphocytes. [1] This complex cellular function is orchestrated by key biomolecules, including HLA receptors, T cell receptors, and various signaling molecules that govern cell-to-cell communication.
Regulatory networks involving specific signaling pathways are crucial for controlling B cell activation, proliferation, and differentiation into antibody-producing plasma cells. For instance, studies indicate the importance of PI3K/Akt signaling and G protein-coupled receptor (GPCR)-mediated pathways in modulating immune responses. [8] These pathways, along with mechanisms controlling the cell cycle, ensure the clonal expansion of activated lymphocytes necessary for a robust antibody response. [8] Genetic variants can influence gene expression patterns and the function of critical enzymes or transcription factors within these pathways, leading to individual differences in antibody production.
Systemic Impact and Pathophysiological Relevance
Variations in the genetic determinants of antibody responses have significant pathophysiological implications, influencing an individual's susceptibility to and the clinical outcome of infectious diseases. A strong antibody response, indicated by higher MFI values, generally correlates with more effective immune protection, whereas a weaker or less specific response might increase vulnerability to infection or lead to more severe disease manifestations. [1] The presence of specific HLA alleles can impact the efficiency of antigen presentation and immune clearance, thereby affecting disease mechanisms at a systemic level and influencing the body's overall ability to maintain homeostasis against pathogens.
These genetic and immunological differences contribute to systemic consequences, shaping an individual's overall immune competence and health profile. Understanding these genetic determinants can illuminate the complex interplay between host genetics and infectious diseases, offering insights that may be leveraged for the development of targeted therapies and more effective vaccines. [1] The recognized influence of environmental and socioeconomic factors alongside genetic predispositions further highlights the multifaceted nature of infectious disease outcomes and immune system regulation. [1]
Immune Signaling and Receptor-Mediated Responses
Seropositivity, indicating a host's immune response to a pathogen, is fundamentally driven by intricate immune signaling pathways that activate cells and coordinate defense mechanisms. Key among these are G-protein coupled receptors (G-PCRs) and their associated signaling cascades, which have been implicated in seropositivity to certain infections, including Chlamydia trachomatis. [8] The activation of these receptors initiates intracellular signaling events, such as the PI3K/Akt pathway and pathways involving Fibroblast Growth Factor Receptors (FGFRs) and Neural Growth Factor Receptors (NGFRs), which play roles in cell cycle control and cellular responses to infection. [8] Furthermore, the Type I interferon signaling pathway, particularly the Interferon alpha/beta signaling pathway and IRF3-mediated induction, is significantly enriched in responses leading to seropositivity for other pathogens, orchestrating cellular defense mechanisms against infections. [6]
These signaling cascades converge to regulate transcription factors, which in turn control the expression of genes crucial for immune function. For instance, the IRF3 pathway is central to regulating type I interferon during bacterial and viral infections, influencing the host's ability to mount an effective antibody response. [6] Beyond direct signaling, the cellular response also involves class I MHC-mediated antigen processing and presentation, where genes like MAP3K3, KLHL3, CFHR4, and CFHR2 are closely related to interferon and complement pathways. [6] The interplay of these receptors and downstream signaling molecules ensures a coordinated and robust immune response, leading to the production of antibodies detectable as seropositivity.
Genetic Regulation of Antibody Production
The intricate process of antibody production and the resulting seropositivity are tightly controlled by host genetic regulatory mechanisms, including gene regulation and the highly polymorphic Human Leukocyte Antigen (HLA) system. Genetic variants, particularly within the MHC region on chromosome 6, are major determinants of antibody-mediated immune responses to infectious agents. [1] These HLA genes encode proteins critical for presenting pathogen-derived antigens to T cells, thereby initiating specific antibody production. Allelic variations and specific amino acid residues within HLA genes significantly influence the repertoire and efficacy of the humoral immune response. [1]
Beyond HLA, other regulatory mechanisms, such as protein modification and post-translational regulation, contribute to shaping the immune response. For example, the transcription factor IRF4 has been shown to promote the activation of certain viruses, indicating its role in influencing the host's interaction with pathogens and subsequent antibody responses. [9] The overall genetic architecture, including elements like Epstein-Barr virus nuclear antigen 1 (EBNA1), contributes to the diverse landscape of human antibody epitope repertoires, which are influenced by genetic, environmental, and intrinsic factors. [10] These regulatory layers ensure specificity and adaptability in the humoral immune response, contributing to the establishment of seropositivity.
Metabolic Reprogramming and Pathway Interplay
Effective immune responses, including antibody production and the establishment of seropositivity, necessitate significant metabolic reprogramming within host cells to meet increased energy demands and biosynthetic requirements. General metabolic pathways are among the top enriched pathways identified in genome-wide association studies related to seropositivity for various pathogens. [6] This metabolic regulation involves adjustments in energy metabolism, biosynthesis of essential molecules, and catabolic processes to support the proliferation and differentiation of immune cells, such as B cells, into antibody-producing plasma cells. The PI3K/ErbB pathway, for instance, is generally related to cell signaling and broader cell metabolism functions, highlighting the integral connection between signaling and metabolic processes in immune cells. [6]
Systems-level integration is evident through extensive pathway crosstalk and network interactions that coordinate metabolic shifts with immune activation. The PI3K/ErbB pathway's involvement suggests a role in nutrient sensing and growth regulation, linking directly to the metabolic state of immune cells. This interplay ensures that immune cells have the necessary resources to mount an effective defense, including the production of antibodies. [6] Such hierarchical regulation and emergent properties arising from these complex networks allow the immune system to adapt its metabolic state to the demands of an ongoing infection, ultimately influencing the magnitude and duration of seropositivity.
Host-Pathogen Interactions and Disease Determinants
The mechanisms underlying seropositivity are critical in understanding host-pathogen interactions and identifying disease-relevant mechanisms, including pathway dysregulation and potential therapeutic targets. Genetic variants associated with seropositivity to various infectious agents often reside in loci that influence the host's susceptibility to infection or the strength of the antibody-mediated immune response. [1] Genome-wide association studies (GWAS) have successfully identified several such loci, particularly within the MHC region, which plays a central role in immune recognition and response. [1] These studies aim to uncover genetic determinants responsible for varying antibody responses within seropositive populations.
Pathway dysregulation can lead to altered immune responses, impacting the ability to clear infection or resulting in chronic conditions. For example, the STING signaling pathway is a crucial component of innate immunity against pathogens, and its selective reactivation can be a therapeutic target in certain contexts. [11] The identification of specific genes and pathways, such as those related to complement (CFHR4, CFHR2) or interferon signaling, provides insights into the molecular basis of seropositivity and potential points for intervention. [6] Understanding these genetic and mechanistic determinants is crucial for developing targeted therapies and vaccines to modulate antibody-mediated immune responses to infectious diseases. [1]
Clinical Interpretation of Bartonella Seropositivity
The clinical utility of Bartonella seropositivity requires careful consideration due to inherent diagnostic limitations of serological tests. A positive antibody titer, particularly if low, may be attributable to cross-reactivity with other antigens, potentially leading to ambiguous or misleading results. [1] Conversely, a negative serological test for Bartonella does not definitively exclude prior exposure or infection, as a host may not have mounted a detectable antibody-mediated response, or antibodies might not serve as a reliable proxy for contact or immune status. [1] Furthermore, Bartonella antibody levels are known to fluctuate over time due to a multitude of host and environmental factors, which complicates the accurate assessment of past exposure or disease activity based on single measurements. [1] These interpretational challenges underscore the need for clinical correlation and careful contextualization of serological findings in patient care.
Genetic Influences on Bartonella Antibody Response
Research into the genetic determinants of antibody-mediated immune responses, including those against pathogens like Bartonella, provides a foundational understanding for personalized medicine approaches and risk stratification. Genome-wide association studies (GWAS) identify specific genetic variants associated with previous infections and variations in antibody responses within seropositive populations. [1] Studies have explored the role of Human Leukocyte Antigen (HLA) genes, such as HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, and HLA-DQB1, as well as specific amino acid residues, in shaping these immune responses. [1] Identifying these genetic predispositions that influence the ability to mount an antibody response could ultimately inform individualized risk assessments and guide prevention strategies for various infectious diseases, including those caused by Bartonella. [1]
Frequently Asked Questions About Bartonella Seropositivity
These questions address the most important and specific aspects of bartonella seropositivity based on current genetic research.
1. Why do some people get sick from Bartonella but I don't, even if we're both exposed?
Your genes play a big role in how your body reacts to infections. Even with the same exposure, genetic differences can make some people more susceptible to getting sick or having a stronger immune response, while others might show no symptoms or clear the infection easily. Research identifies specific genetic variations that influence this individual variability.
2. If my family has a history of infections, am I more likely to get Bartonella?
Yes, your family's genetic background can influence your susceptibility. Because genetic factors determine how your immune system responds to infections, if your family shares certain genetic predispositions, you might have a similar tendency for how your body handles Bartonella exposure. This is why genetic studies look for inherited variants linked to infection risk.
3. Can my genes make my Bartonella symptoms worse than someone else's?
Absolutely. Your genes can influence how severe your Bartonella infection might be. Genetic factors not only affect your susceptibility to getting infected but also modulate your immune response, which can impact disease progression and the severity of symptoms you experience. This means some people are genetically predisposed to a more severe illness.
4. Does my ancestry affect my risk for Bartonella?
Yes, your ancestry can definitely play a role. Genetic predispositions and how your immune system responds to infections, including specific immune system genes, can vary significantly across different ancestral backgrounds. Research often focuses on specific populations, and findings might not directly apply to all ethnicities, highlighting the need for diverse studies.
5. If my test shows I have Bartonella antibodies, does it mean I'm sick now?
Not necessarily. Detecting Bartonella antibodies means your immune system has been exposed to the bacteria at some point, either in the past or currently. It doesn't always confirm an active infection, as antibodies can persist after an infection clears, or sometimes tests show low-level binding that isn't a true infection. Your doctor would combine this with your symptoms for a diagnosis.
6. Can my daily habits influence how my body fights Bartonella?
Yes, your daily habits and environment can definitely influence your immune response to Bartonella. While genetics play a role, non-heritable factors like your overall health, nutrition, and exposure to the bacterium in your environment are significant determinants of infectious diseases. These factors can dynamically impact your antibody levels and your body's ability to fight off infections.
7. If I've been exposed, why might my antibody levels be low compared to others?
Your antibody levels can vary greatly due to both genetic and environmental factors. Your unique genetic makeup influences how strongly your immune system responds and produces antibodies after exposure. Additionally, other host factors and environmental influences can dynamically affect these levels, meaning some individuals naturally produce lower or higher amounts of antibodies.
8. Could a DNA test tell me if I'm more susceptible to Bartonella?
Potentially, yes. Research is actively identifying specific genetic variants that are linked to a higher susceptibility to Bartonella infection or to how your immune system responds. While not yet a standard diagnostic tool for individual risk, genetic studies aim to pinpoint these markers to help identify individuals who might be at higher risk for developing the disease.
9. Does understanding my genes help prevent Bartonella?
Understanding the genetic factors influencing Bartonella susceptibility helps at a broader public health level right now. While it's not a direct personal prevention tool yet, these insights inform strategies for disease prevention and control, and can lead to more targeted public health interventions. In the future, it might help identify high-risk individuals for more personalized prevention.
10. Does living in a certain area increase my Bartonella risk?
Yes, where you live significantly impacts your risk of exposure to Bartonella. The bacteria are often transmitted by arthropod vectors like fleas, ticks, and lice, which are more prevalent in certain geographic areas and environments. Therefore, your local environment plays a crucial role in whether you encounter these vectors and thus the bacterium.
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
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[5] Ishigaki, Kazuyoshi, et al. "Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis." Nature Genetics, vol. 54, no. 12, 2022, pp. 1827–41.
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[7] Hodel, F. "Human genomics of the humoral immune response against polyomaviruses." Virus Evol, 2021.
[8] Roberts, C. H., et al. "Conjunctival fibrosis and the innate barriers to Chlamydia trachomatis intracellular infection: a genome wide association study." Scientific Reports, vol. 5, no. 1, 2015, article 17447.
[9] Gao, Y., et al. "IRF4 promotes Epstein-Barr virus activation in Burkitt’s lymphoma cells." J Gen Virol, vol. 100, 2019, pp. 851–62.
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[11] Liu, W., et al. "Selective reactivation of STING signaling to target Merkel cell carcinoma." Proc Natl Acad Sci U S A, vol. 117, 2020, pp. 13730–9.