Genetic Dissection of arenavirus-induced lethality

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 DESCRIPTION (provided by applicant): Hemorrhagic fever viruses cause severe clinical manifestations with high case fatality rates and are serious bioterrorism threats. Among them, Lassa virus (LASV) is the second most common cause of hemorrhagic fevers worldwide, infects hundreds of thousands of individuals annually, culminating in ~5,000 to 20,000 deaths per year. There is no approved vaccine and treatment options are limited. The main characteristics of Lassa and other hemorrhagic fevers are endothelial damage, platelet loss and vascular leakage, leading to tissue edema, organ failure and death in severe cases. However, how differences in immune and endothelial cell responses to LASV might affect vascular integrity, and the genetic basis for susceptibility to severe disease, have not been defined. We recently showed that the lymphocytic choriomeningitis virus (LCMV) variant Cl13, considered a model of LASV, causes in NZB mice (but not in B6 mice) severe IFN-dependent vascular leakage, platelet loss, and death, the main characteristics of hemorrhagic fevers. In additional studies we showed that F1 crosses of NZB and B6 are also susceptible, while F1xB6 backcrosses showed 54% mortality, a pattern compatible with Mendelian dominant inheritance of susceptibility. This proposal will 1) use DNA from affected and non-affected backcrosses to identify for the first time a gene that controls susceptibility to arenavirus-induced lethality, and 2) confirm the relevance of the identified gene by imposing this mutation in non-susceptible B6 mice. The identified gene might encode a molecule previously unrecognized as being a contributor to virus-induced immune and vascular dysfunctions. Thus, the proposed study holds the potential of revealing new mechanistic insights, genetic basis, and molecular targets of therapeutic intervention for Lassa and other viral HF syndromes.