RESUMEN
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 and study populations are often limited in demographic diversity. Utilizing samples from 1,705 individuals in 5 countries, we examined putative determinants of immunity, including: single nucleotide polymorphisms, ancestry informative markers, herpesvirus status, age, and sex. In healthy subjects, we found significant differences in cytokine levels, leukocyte phenotypes, and gene expression. Transcriptional responses also varied by cohort, and the most significant determinant was ancestry. In influenza infected subjects, we found two disease severity immunophenotypes, largely driven by age. Additionally, cytokine regression models show each determinant differentially contributes to acute immune variation, with unique and interactive, location-specific herpesvirus effects. These results provide novel insight into the scope of immune heterogeneity across diverse populations, the integrative effects of factors which drive it, and the consequences for illness outcomes.