Host Factors for Rhinovirus

PROJECT ABSTRACT We aim to define host factors that are associated with the more virulent human rhinoviruses (RV), RV-A and RV- C. Although RV are the most frequent cause of the common cold, they also provoke more severe manifestations, particularly in those with underlying lung disease. RV are the most frequent cause of asthma exacerbations, specifically induced by RV-A and RV-C, and only rarely RV-B. We have found that RV-A and RV-C require the host factor Stimulator of Interferon Genes (STING) for replication of their genome, while RV-B do not. Although STING is an immune adaptor critical for immune sensing in DNA viruses, its importance during RNA infections is becoming increasing recognized. In humans, STING1 exists as multiple variant alleles containing one or more single nucleotide polymorphisms. The most common STING variant is deficient in type I interferon (IFN-I) signaling, while other common variants have reduced IFN-I. As RV are restricted to only infect humans, we have found that for RV-A and RV-C, STING is a restricting host factor. While human STING robustly supports RV-A and RV-C replication, murine STING does not. The three Aims of the Project will explore the mechanism for STING host factor activity, determine how natural STING alleles influence RV-A and RV-C replication, and identify which nonstructural components of the virus interact with STING or the STING complex to promote infection. By studying the host factor role of STING during RV replication, the proposed research will define factors important for the increased virulence between RV species in this important human pathogen.