Innate immune responses are induced by specific interactions between pathogen-associated molecules and Toll-like receptors (TLRs), and are critical to host defense. Recent studies have shown a role for TLR7 and TLRS in innate immune responses to viral infection. However, it is unknown to what extent these innate immune responses are heritable and what loci might affect this heritability. Our overall hypothesis is that heritable variation exists in gene expression levels measured during an innate immune response to virus-associated molecules. We propose to study this hypothesis in the context of innate immune responses to synthetic agonists specific for TLR7 (imiquimod) or both TLR7 and TLR8 (R848). First, we will determine genome-wide heritability of R848-induced changes in gene expression using a classical twins study. We will then identify quantitative trait loci (QTL) that control heritable variation in TLR7-induced gene expression in B-lymphoblastoid cell lines (B-LCL) isolated from 'HapMap'trios, and we will fine-map the functional polymorphisms within these QTL in a large cohort of healthy individuals. Finally, we will apply in vitro assays of promoter function and RNA processing to understand how these polymorphisms affect gene expression. The proposed studies will identify specific genetic loci controlling heritability of TLR7/8- mediated innate immune responses and more broadly, basic mechanisms underlying the genetic control of gene expression in environmentally perturbed cells. Results from these studies will provide novel potential markers of susceptibility for both common and emerging viral infection and will characterize a new experimental pathway for discovery of functional genetic variation affecting responses to environmental stimuli.
