Integrated drivers of basal and acute immunity in diverse human populations

Prior studies have identified genetic, infectious, and biological associations with immune competence and disease severity; however, there have been few integrative analyses of these factors. Here, we examine putative determinants of immunity, including single-nucleotide polymorphisms, genetic ancestry, race/ethnicity, herpesviruses, age, and gender. Healthy cohorts exhibit significant differences in cytokine levels, leukocyte phenotypes, and gene expression. Transcriptional responses post cell stimulation also vary by cohort, and major determinants include herpesviruses, genetics, and race/ethnicity. In subjects with acute influenza, there are two distinct disease severity immunophenotypes, largely driven by age. Additionally, cytokine regression models, including correlates of severity, show that each determinant differentially contributes to immune variation, with unique and interactive, location-specific herpesvirus effects. These results provide valuable insight into the scope of basal and acute immune heterogeneity across diverse populations, the relationship between these two immune states, the integrative effects of factors that drive it, and the consequences for illness outcomes.