Genetic control of alphavirus pathogenesis

Abstract

Alphaviruses, members of the positive-sense, single-stranded RNA virus family Togaviridae, represent a re-emerging public health concern worldwide as mosquito vectors expand into new geographic ranges. Members of the alphavirus genus tend to induce clinical disease characterized by rash, arthralgia, and arthritis (chikungunya virus, Ross River virus, and Semliki Forest virus) or encephalomyelitis (eastern equine encephalitis virus, western equine encephalitis virus, and Venezuelan equine encephalitis virus), though some patients who recover from the initial acute illness may develop long-term sequelae, regardless of the specific infecting virus. Studies examining the natural disease course in humans and experimental infection in cell culture and animal models reveal that host genetics play a major role in influencing susceptibility to infection and severity of clinical disease. Genome-wide genetic screens, including loss of function screens, microarrays, RNA-sequencing, and candidate gene studies, have further elucidated the role host genetics play in the response to virus infection, with the immune response being found in particular to majorly influence the outcome. This review describes the current knowledge of the mechanisms by which host genetic factors influence alphavirus pathogenesis and discusses emerging technologies that are poised to increase our understanding of the complex interplay between viral and host genetics on disease susceptibility and clinical outcome.

Fig. 1

Approaches for studying the role of host genetics on alphavirus pathogenesis. a Loss of function screen using siRNA to knockdown host gene expression. b Examination of differential gene expression in alphavirus-infected versus mock-infected mouse tissues using microarray. c Quantification of relative amounts of transcripts in alphavirus-infected versus mock-infected mouse tissues using RNA-sequencing (RNA-Seq). d Examination of the effect of individual genes on alphavirus pathogenesis through candidate gene studies. YFG your favorite gene

Fig. 2

Systems genetics approach to studying the role of host genetics on alphavirus pathogenesis using the Collaborative Cross (CC). a CC mouse populations are created by crossing eight inbred founder lines (yellow = A/J, gray = C57BL/6J, pink = 129S1/SvlmJ, dark blue = NOD/ShiLtJ, light blue = NZO/HiLtJ, green = CAST/EiJ, red = PWK/PhJ, purple = WSB/EiJ) and then inbreeding them to create a panel of fully reproducible lines. b In a model experiment, mice from different CC lines are infected with an alphavirus, and c disease phenotypes are evaluated across all infected CC lines. d QTL mapping is used to identify genome regions that contribute to phenotypic variation among alphavirus-infected CC lines. A QTL associated with variation in clinical disease severity is identified within chromosome 10, with the lower red line indicating p = 0.1 and the upper red line indicating p = 0.05. e An allele effects plot for the QTL shows that the locus is primarily driven by a WSB/EiJ founder effect. f Sequence data for genes within the QTL can be accessed using the Sanger Mouse Genomes Database (https://www.sanger.ac.uk/sanger/Mouse_SnpViewer/rel-1303) to identify haplotypes across the eight founder strains (Haplotype 1 = A/J, C57BL/6J, 129S1/SvlmJ, CAST/EiJ, PWK/PhJ; Haplotype 2 = NOD/ShiLtJ, NZO/HiltJ; Haplotype 3 = WSB/EiJ). Polymorphisms are denoted by arrows, with coding changes denoted by large arrows, and noncoding changes denoted by small arrows. Founder strains possessing each polymorphism are denoted by colors indicated above. g Candidate gene studies are performed to better understand the contribution of specific genes within the QTL to the phenotype in question. (Color figure online)