Heterogeneity in the human immune system can lead to limited vaccine efficacy, poor response to therapeutics, increased susceptibility to immune mediated diseases, and differential outcome to infection. Studies to date have suggested a role for biological, environmental, and genetic factors in immune variation; however, they are often focused on a specific subset of the population (e.g. ancestral group, age range) which can exclude phenotypes unique to a diverse population and bias results. To address this gap, we have utilized samples from healthy or influenza virus infected subjects from 8 distinct populations in 5 countries to conduct an integrative analysis of the unique and interactive effects of age (biological), herpesvirus serostatus (environmental), and genetics on variation in basal immunity and acute responses. At baseline, we have found differences between diverse populations in plasma cytokine levels, circulating leukocyte phenotypes, CD8 T cell receptor repertoires, and gene expression. Variation was observed for growth factors, chemokines, immunomodulators, and proinflammatory cytokines. Additionally, compared to Nicaraguans, Memphians exhibit higher activated myeloid and lymphoid subsets, and have CD8 T cell receptor repertoires which are significantly more clonal and less diverse. Moreover, analysis of peripheral blood mononuclear cell gene expression, after stimulation with pathogen recognition receptor ligands representative of bacterial or viral infection, shows differential responses dependent on condition and cohort. With respect to genetics, an analysis of 94 single nucleotide polymorphisms (SNPs) illustrates significant differences in minor allele frequencies in immune related genes with potential effects on transcription, as 38 were expression quantitative trait loci (eQTL) in 26 genes (25 cytokines and 1 transcription factor). Importantly, variation in the expression of immune transcription factors and effector molecules coupled with variation in the differentiation of leukocyte subsets may lead to differences in acute immune responses. Results from subjects with naturally acquired influenza infection show herpesviruses are largely beneficial and improve illness outcome. Herpes simplex virus is associated with decreased duration of influenza virus shedding, and cytomegalovirus is associated with increased functional antibody titers and decreased symptom severity scores. Utilizing a regression model to account for age, sex, herpesviruses, and genetics, we found herpesviruses have unique and interactive effects on cytokine levels that are specific to anatomical location. Additionally, of the 25 cytokines with an eQTL, 11 had significant genetic influence during flu infection. Interestingly, all 11 of these cytokines were identified as correlates of severity in an analysis of 4 independent populations. Furthermore, associations between cytokine levels and influenza severity were consistent in cohorts of similar ancestral and environmental backgrounds or age range, and several unique correlates were identified for each population. Lastly, utilizing mouse models of influenza and murine cytomegalovirus (MCMV) co-infection, we have found co-infection augments innate immunity and enhances functional CD8 T cell responses against influenza epitopes, but impairs MCMV-specific responses. These data suggest prior infection with herpesviruses are beneficial to acute infection, but the reciprocal effects of heterologous infections on herpesvirus immunity are detrimental and may lead to eventual loss of herpesvirus control. Together, these results provide novel insight into the scope of immune variation across diverse populations, the unique and interactive effects of factors which drive immune heterogeneity, the subsequent consequences on differential outcome during infection, and how prior infectious exposures can affect acute immune responses.
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