Common Genetic Variation Influences the Immune Response to Viral Infections in Human Populations

Humans show remarkable differences in susceptibility to many infectious diseases, and in part, this heterogeneity arises from variation in the immune response following infection. The immune response to infection is a complex, dynamic process that involves the coordinated action of multiple cell types to recognize and eliminate a pathogen. Genome-wide association studies and expression quantitative trait loci (eQTL) mapping studies in immune cells have shown that certain polymorphisms drive variation in the response to viruses in specific contexts. Yet, little is known about how genetic ancestry and genetic variation affect the immune response to viral infection more broadly. We generated single-cell RNA-sequencing data in multiple disease contexts, including in vitro infection with influenza A virus and in vivo infection with SARS-CoV-2, and mapped eQTL to study the genetic architecture of gene expression in these various settings. Following influenza infection, we showed that genetic ancestry effects on gene expression were common, highly cell type-specific, and often explained by cis-eQTL. Among hospitalized COVID-19 patients, we demonstrated that a substantial proportion of all cis-eQTL identified showed a significant gene-environment interaction effect: either they were observed only in monocytes of SARS-CoV-2-infected individuals or were associated with functional cell state. Together, our findings establish common cis-regulatory variants as key determinants of the response to viral infection, highlight the ubiquitous nature of gene-environment interactions in the framework of an immune response, and underscore the need to study regulatory processes in relevant cell types and disease states.