Oas1b-dependent Immune Transcriptional Profiles of West Nile Virus Infection in the Collaborative Cross

Abstract

The oligoadenylate-synthetase (<i>Oas</i>) gene locus provides innate immune resistance to virus infection. In mouse models, variation in the <i>Oas1b</i> gene influences host susceptibility to flavivirus infection. However, the impact of <i>Oas</i> variation on overall innate immune programming and global gene expression among tissues and in different genetic backgrounds has not been defined. We examined how <i>Oas1b</i> acts in spleen and brain tissue to limit West Nile virus (WNV) susceptibility and disease across a range of genetic backgrounds. The laboratory founder strains of the mouse Collaborative Cross (CC) (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, and NZO/HlLtJ) all encode a truncated, defective <i>Oas1b</i>, whereas the three wild-derived inbred founder strains (CAST/EiJ, PWK/PhJ, and WSB/EiJ) encode a full-length OAS1B protein. We assessed disease profiles and transcriptional signatures of F1 hybrids derived from these founder strains. F1 hybrids included wild-type <i>Oas1b</i> (F/F), homozygous null <i>Oas1b</i> (N/N), and heterozygous offspring of both parental combinations (F/N and N/F). These mice were challenged with WNV, and brain and spleen samples were harvested for global gene expression analysis. We found that the <i>Oas1b</i> haplotype played a role in WNV susceptibility and disease metrics, but the presence of a functional <i>Oas1b</i> allele in heterozygous offspring did not absolutely predict protection against disease. Our results indicate that <i>Oas1b</i> status as wild-type or truncated, and overall <i>Oas1b</i> gene dosage, link with novel innate immune gene signatures that impact specific biological pathways for the control of flavivirus infection and immunity through both <i>Oas1b</i>-dependent and independent processes.