Abstract
Infectious diseases and autoimmune diseases, such as multiple sclerosis (MS) and type 1 diabetes (T1D), have traditionally been seen as distinct, with separate etiologies and courses of disease. Recent research has shown that infection and autoimmune disease are more closely woven together than previously thought; certain pathogens like Epstein-Barr virus and M. tuberculosis have been shown to cause long-term disruption to the immune system, for example (Bordignon et al 2011, #1) (Zhang et al 2023, #2) (Bjornevik et al 2023, #3). Conversely, a distinct pattern has emerged in developed countries where as rates of infection fall, rates of autoimmune disease climb, suggesting that infection in early childhood can protect against later immune dysfunction (Bach et al 2002, #4). This has been termed the hygiene hypothesis. Regardless of the directionality of the relationship, it is clear that autoimmune disease and infectious disease are not the completely separate entities they've traditionally been viewed as. Research has found that infection likely acts as one of many factors that make someone susceptible to autoimmune disease. Many of the pathogens implicated in autoimmune disease are ubiquitous and do not always cause symptomatic disease, suggesting that for each individual it is some combination of exposures, infections, and genetic predispositions that together cause autoimmune disease. However, even if infection does not independently cause autoimmune disease, the role it plays is nevertheless important, and specific evidence and observed mechanisms support the concept of infection acting as a trigger or accelerant for autoimmune disease. The proposed mechanisms for this to occur include molecular mimicry, bystander activation, epitope spreading, the action of overexpressed costimulatory molecules, and the effects of superantigens, among others. Complex autoimmune diseases like multiple sclerosis or type one diabetes lack a single unifying cause. Previous research (Bach et al 2005, #5) indicates that genetic risk factors, hormonal differences, environmental exposures, and other unknown factors likely work in combination to create autoimmune disease. Leveraging large-scale genetic studies like phenome-wide association studies (PheWAS) and genome-wide association studies (GWAS) enables researchers to begin to identify patterns in etiology and determine the contributions of many different genetic and environmental factors to disease risk. PheWAS studies identify associations between an exposure or single genetic variant and the entire phenome, and GWAS studies identify associations between an exposure or single genetic variant and the entire genome. Elucidating the etiology of complex diseases requires processing huge datasets and scanning the entire genome or phenome, since individual factors are unlikely to significantly alter risk. Aim 1: Assess the relationship between infection and other complex diseases via PheWAS. In order to continue to unravel the multifaceted association between infection and other complex diseases, we will perform a PheWAS on two infectious diseases, herpes simplex virus infections (HSV1 and HSV2) and Mycobacterium tuberculosis infections, with the goal of identifying subsequent diseases. We will perform our research in the All of Us dataset, using the electronic health record (EHR) data, which includes 10,000 cases of herpes simplex virus infection and 8,000 cases of M. tuberculosis. We will use age and sex as covariates and stratify our analysis by genetic ancestry. Aim 2. Assess the role of genetic predisposition in acquiring a diagnosed herpes simplex virus or Mycobacterium tuberculosis infection. Susceptibility to complex disease is both genetic and environmental in nature, and genetic susceptibility to complex disease could actually be mediated by infection. In order to begin to define this relationship, we will perform a GWAS on infection with these two pathogens to screen for genetic variants that could contribute to infection, using the same dataset as in Specific Aim 1. By comparing the variants linked to infection and the variants linked to complex disease, we hope to identify variants implicated in both, further weaving together the pathogenesis of complex disease and infection. We will again use age and sex as covariates and stratify by genetic ancestry.
Degree
MS
College and Department
Life Sciences; Microbiology and Molecular Biology
Rights
https://lib.byu.edu/about/copyright/
BYU ScholarsArchive Citation
Howell, Lydia, "The Long Shadow of Infection: The Long-Term Implications of Herpes Simplex Virus and M. Tuberculosis Infection" (2024). Theses and Dissertations. 11122.
https://scholarsarchive.byu.edu/etd/11122
Date Submitted
2024-12-10
Document Type
Thesis
Keywords
PheWAS, GWAS, chronic disease, herpes simplex virus, M. tuberculosis, infection, autoimmunity, electronic health record data, genomics
Language
english