Contribution of a Major Quantitative Trait Locus to Mouse Adenovirus Type 1 Encephalitis and Mortality

Abstract

Mice from susceptible mouse strains die from hemorrhagic encephalomyelitis following infection with mouse adenovirus type 1 (MAV-1). MAV-1 susceptibility quantitative trait locus, Msq1, was identified based on its strong linkage to the high brain viral load phenotype (a surrogate measure of susceptibility) following MAV-1 infection. Msq1 accounts for ~40% of the phenotypic trait variance between resistant BALB/c and susceptible SJL mice after MAV-1 infection. To study the in vivo contribution of Msq1, we bred an interval-specific congenic mouse strain (C.SJL-Msq1SJL), in which the SJL-derived allele Msq1SJL is introgressed onto a BALB/c background. Msq1SJL accounts for the high brain viral titers and blood-brain barrier disruption, yet does not account for the total extent of brain pathology, edema, inflammatory cell recruitment or mortality in SJL mice. In comparison, BALB/c mice showed no signs of disease 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. These results validate Msq1 as an important host factor in MAV-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. There are 14 Ly6 or Ly6-related genes in Msq1, which spans from 74.68 to 75.43 Mb on mouse chromosome 15. Ly6 genes are good candidate genes for MAV-1 susceptibility because their gene products are expressed on both myeloid and lymphoid cells and because they can be upregulated by both type I and II interferons. In addition, they have been identified as important host factors in other viral infections, including HIV, West Nile virus and Marek’s disease virus. To identify the specific Ly6 gene(s) that influence MAV-1 infection, transgenic mouse strains were made using bacterial artificial chromosomes derived from Msq1129S6/SvEv. Thus far, 7 of the 8 transgenic mouse strains were phenotypically resistant to MAV-1 infection. Efforts to interpret the resistant phenotype are currently ongoing.