A forward genetic analysis of a lethal arenavirus infection

Arenaviruses can cause severe hemorrhagic disease in humans although the underlying mechanisms causing lethality and person-to-person variation in outcome remain incompletely explained. Herein, we have developed a mouse model that recapitulates many features of pathogenesis observed in humans with arenavirus-induced hemorrhagic disease, including thrombocytopenia, severe vascular leakage, lung edema, and lethality. The susceptibility of B6.PL mice to LCMV infection was dominant in F1 crosses with non-susceptible B6 mice and was associated with gene expression in hematopoetic cells. Pathogenesis was associated with increased antiviral T cell responses in B6.PL mice compared to B6 mice and was T cell-dependent. Forward genetics and deep sequencing revealed a 20Mb region on chromosome 9 that is responsible for severe pathogenesis, which included several deleterious mutations in immune-related genes. This reproducible mouse model can be used to further interrogate how host genetics, innate and adaptive immune responses, and environmental influences determine disease outcome.