Genetic and Infectious Regulators of Baseline and Acute Immunity Across Ancestrally Distinct Human Populations

Abstract

Studies have identified genetic, viral, and immunological associations with the quality of anti-influenza immunity and/or influenza disease severity, however, there has not been an integrative analysis of these factors, both at baseline and during acute infection. Using samples from healthy or flu infected human cohorts across 5 countries, we found that herpesviruses (HVs) have unique and interactive effects on cytokine levels specific to anatomic location during flu infection. Similar cytokine associations were also observed in healthy controls. Additionally, HV infection is also associated with decreased flu severity and virus shedding, and increased antibody titers. Associations between cytokine levels and flu severity were consistent in cohorts of similar ancestral and environmental backgrounds, however unique correlates were observed in populations from distinct backgrounds. Further, we identified ~100 variants in immune related genes either enriched in or absent from a given ancestral population, a portion of which are eQTLs at baseline, supporting the potential of host genetics to impact immune variation. Ongoing work focuses on assessing which SNPs are eQTLs in response to bacterial and viral TLR agonists. Ancestry informative marker PCA values and eQTLs will be included in the statistical models to account for the collective effects of infectious, biological, and genetic factors. These results will provide insight into which factors predominantly affect a given immune measure and how this contributes to immune competence and variation across distinct populations. Understanding these interactions will have implications for other infectious diseases, autoimmunity, clinical study design, and immunotherapy.