Contribution of a Single Host Genetic Locus to Mouse Adenovirus Type 1 Infection and Encephalitis

ABSTRACT Susceptibility to mouse adenovirus type 1 (MAV-1) is mouse strain dependent; susceptible mice die from hemor-rhagic encephalomyelitis. TheMAV-1 susceptibility quantitative trait locusMsq1 accounts for ~40 % of the phenotypic (brain viral load) variance that occurs between resistant BALB/c and susceptible SJL mice after MAV-1 infection. Using an interval-specific congenic mouse strain (C.SJL-Msq1SJL), in which the SJL-derived alleleMsq1SJL is present in a BALB/c background, we demonstrate thatMsq1SJL controls the development of high brain viral titers in response toMAV-1 infection, yet does not ac-count for the total extent of brain pathology or mortality in SJL mice. C.SJL-Msq1SJL mice had disruption of the blood-brain bar-rier and increased brain water content after MAV-1 infection, but these effects occurred later and were not as severe, respec-tively, as those noted in infected SJL mice. As expected, BALB/c mice showedminimal pathology in these assays. Infection of SJL-and C.SJL-Msq1SJL-derived primary mouse brain endothelial cells resulted in loss of barrier properties, whereas BALB/c-derived cells retained their barrier properties despite being equally capable of supportingMAV-1 infection. Finally, we provide evidence that organ pathology and inflammatory cell recruitment to the brain followingMAV-1 infection were both influenced byMsq1. These results validateMsq1 as an important host factor inMAV-1 infection and refine the major role of the locus in development of MAV-1 encephalitis. They further suggest that additional host factors or gene interactions are involved in the mechanism of pathogenesis in MAV-1-infected SJL mice. IMPORTANCE A successful viral infection requires both host and viral factors; identification of host components involved in vira