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

The oligoadenylate-synthetase () gene locus provides innate immune resistance to virus infection. In mouse models, variation in the gene influences host susceptibility to flavivirus infection. However, the impact of variation on overall innate immune programming and global gene expression among tissues and in different genetic backgrounds has not been defined. We examined how 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 , 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 (F/F), homozygous null (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 haplotype played a role in WNV susceptibility and disease metrics, but the presence of a functional allele in heterozygous offspring did not absolutely predict protection against disease. Our results indicate that status as wild-type or truncated, and overall gene dosage, link with novel innate immune gene signatures that impact specific biological pathways for the control of flavivirus infection and immunity through both -dependent and independent processes.