PROJECT ABSTRACTRhinovirus (RV) infections are ubiquitous across age gender and ethnicity and are the most frequent reasonfor healthcare visits. In the majority of affected persons the symptoms of RV infections are mild and self-limiting.In persons with chronic rhinosinusitis (CRS) however RV infections are a major cause of CRS exacerbationsand associated morbidity. Recently we found that RV-C species are common in adults and that RV-C infectionsresult in greater sinonasal symptoms compared with the well-studied RV-A and RV-B species. We alsodetermined that rs6967330 a genetic risk variant in the recently discovered RV-C Cadherin Related FamilyMember 3 (CDHR3) viral receptor causes a two-fold increase in the odds for adult CRS. Although CRS is aheterogeneous disorder transcriptome studies of surgical tissues have determined significant dysregulation ofgenes associated with chemokine/cytokine signaling and epithelial-mesenchymal transitions (EMT). Theobjective of this application is to (i) determine if subjects with CRS and the rs6967330 CDHR3 risk allelehave a different molecular endotype in response to RV-C infections as compared with those with themore frequent wild-type allele and (ii) determine if adult CRS subjects with the rs6967330 allele are morelikely to have CRS exacerbations with RV-C infections compared to RV-A and RV-B infections. Wehypothesize that in vitro studies of air-liquid-interface (ALI) cultures with the rs6967330 CDHR3 risk allele willgenerate a molecular endotype characterized by (i) increased RV-C binding and replication ii) increasedcytokines/chemokines associated with types 1 and 2 immunity and iii) differentially expressed genes (DEGs)and EMT pathways associated with airway remodeling compared to epithelia expressing the wild-type allele.Likewise we hypothesize that our in vivo studies of CRS subjects with the rs6967330 allele will reveal anincreased number of CRS exacerbations secondary to RV-C infections that are characterized by increasedsinonasal symptoms nasal cytokine production and transcriptomic changes in airway remodeling after infection.There is a critical need to understand the molecular mechanisms that underlie the increased pathogenicity ofRV-C infections in persons with the rs6967330 CDHR3 risk allele to inform the development of new targetedstrategies to prevent and slow the progression of CRS.