West Nile virus infection in the Collaborative Cross mouse model recapitulates unique human disease states

Abstract

Abstract West Nile Virus (WNV) is a cytopathic neurotropic flavivirus that causes a wide range of infection states in humans, ranging from asymptomatic to severe neuroinvasive disease. This variation supports the idea that host genetics play an important role in immunity to WNV infection. The significant individual to individual variation in immune responses within the human population can not be fully captured in single laboratory inbred strains, so a systems genetic approach requires the use of the Collaborative Cross (CC) mouse system to identify polymorphic host genes and networks that control the regulation of adaptive immunity to WNV infection. The CC is a panel of lines with over 40 million single nucleotide polymorphisms evenly distributed throughout the genome, providing the statistical power to map multiple genetic factors with small to moderate effect. In the CC model we have identified lines with unique human phenotypes that have not previously been captured in laboratory inbred strains, such as severe neuroinvasive disease and chronic WNV infection. Our use of the CC model shows differing immune responses to WNV in terms of T cell frequency and activation, antigen-specific CD8 T cell frequency, memory precursor cells, and T cell cytokine production between CC strains after WNV infection. A distinct immune signature is present in the chronic line, characterized by a strong systemic regulatory T cell response and late virus-specific response in the CNS due to viral persistence. Microarray analysis on spleen and CNS tissue reveals expression changes correlated with extreme immune phenotype responses within and between organ compartments, allowing for identification of correlates of protection and susceptibility to WNV infection.