Identifying host genetic determinants that regulate dendritic cell activation

Emory University, Atlanta GA

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Abstract

? DESCRIPTION (provided by applicant): Host genetic diversity can have a strong impact on susceptibility to viral infection and disease severity. For instance, studies with West Nile virus (WNV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), as well as other viral infections in humans, have identified causal genetic variants that influence viral replication, tissue tropism, disease severity, and infection outcome. However, narrow windows of symptoms, combined with confounding environmental factors, have made it difficult to dissect the genetic mechanisms underlying immunity, pathogenesis and infection outcome. Recent international efforts have developed a novel mouse genetic resource, called the Collaborative Cross (CC), designed to model the complexities of the human genome and support an integrative systems genetics approach to understand complex human diseases (e.g. host response to virus infection). The CC is the only mammalian resource with an infinitely reproducible population comprised of high and uniform genome wide variation. In fact, the CC is being used to study diverse medically-relevant traits, including obesity, psychiatric disorders, cancer, autoimmunity, as well as to identify risk factors of fungal, bacterial, and viral infection. At this time, little is known about how genetic diversity influences innate immune signaling in response to virus infection and vaccination. We seek to address this gap in our knowledge. We hypothesize that host genetic variation impacts innate immune sensing and antiviral responses within dendritic cells (DCs). The RIG-I like receptors (RLRs) are pattern recognition receptors that are essential for inducing type I interferon (IFN), antiviral gene expression and promoting B and T cell immunity in response to WNV and other RNA virus infections. We recently observed that WNV-infected primary mouse embryonic fibroblasts derived from the eight CC founder strains exhibited differences in kinetics and magnitude of IFN-ß induction. Through a preliminary screen to evaluate RIG-I signaling within DCs derived from a set of CC lines, we identified a hyper-responsive (AU8005 17.8 fold increased) and hypo-responsive CC line (OR3032- 9.8 fold decreased) that differentially triggered IFN-ß expression relative to C57BL/6J mice. In support of our findings, a recent analysis within human monocytes and DCs identified causal genetic variants that impact toll-like receptor signaling and the antiviral response to influenza virus infection. To investigate our hypothesis, we will use an interdisciplinary approach involving genetics, immunology, virology, and systems biology to identify genetic variants that regulate RLR signaling and DC innate immune responses. Specifically, we will: 1) investigate the impact of genetic diversity on innate immune sensing; and 2) identify genetic variants that regulate RLR signaling in DCs. These studies will provide a greater insight into host genetics and innate immune signaling and establish a foundation for development of immune-modulatory drugs that can more efficiently activate the innate-adaptive immune interface across a wide range of genetic backgrounds.