Impact of Host Genetic Variants on Regulating Chikungunya Virus-Induced Disease

PROJECT ABSTRACT Chikungunya virus (CHIKV) is an emerging mosquito-borne alphavirus that causes major epidemics of both acute and chronic arthralgia. Humans exhibit significant variation in CHIKV disease susceptibility, with outcomes ranging from severe debilitating arthritis to asymptomatic infection. There is growing evidence that polymorphic human genes contribute to variation in disease outcome, however, results from large unbiased genetic mapping studies have not been reported from CHIKV infected humans. Therefore, much of our knowledge of how specific host genes affect CHIKV disease susceptibility comes from mouse models of CHIKV-induced arthritis/myositis. Although standard inbred mouse strains (e.g. C57BL/6 mice) are a valuable resource for studying CHIKV pathogenesis, these mouse strains do not recapitulate many aspects of human genetic diversity, and therefore fail to reproduce the full range of CHIKV-induced disease phenotypes observed in human populations. Therefore, to broaden the phenotypic range of CHIKV-induced disease and study the role of host genetic variation in driving CHIKV disease outcomes, we have used the Collaborative Cross (CC) mouse genetic reference population. CC mice exhibit strain dependent variation in CHIKV disease susceptibility, with outcomes ranging from mild to severe disease, while one outlier strain, CC026, is completely resistant to CHIKV disease. Gene mapping studies identified a quantitative trait locus (QTL) on chromosome 8 (HrCHK1) that regulates susceptibility to CHIKV-induced joint swelling and arthritis. Therefore, as part of this exploratory R21 application, we propose to identify and validate the specific causal gene under HrCHK1 that regulates CHIKV disease outcomes, while performing additional focused mapping studies to identify the specific gene(s) that confer extreme disease resistance on the CC026 genetic background. These studies will significantly advance our understanding of how host genetic variation affects CHIKV susceptibility, while setting the stage for future mechanistic studies focused on understanding how specific gene variants impact CHIKV disease and whether these genes can be targeted to treat acute or chronic alphavirus-induced arthritis.