Project Summary / Abstract Lassa virus and Ebola virus are two of the most devastating human pathogens and infection with both can lead to severe hemorrhagic fever with case fatality rates in excess of 70%. It is estimated that tens of thousands of people die from Lassa fever each year. Despite the high case fatality rates of hospitalized Ebola and Lassa fever patients, it is well established that asymptomatic or mildly symptomatic infections occur in both Lassa fever and Ebola. We know that virus genetics play key roles in determining disease severity, however, mechanistic insights are lacking and no systematic studies have been performed to identify virus correlates of human disease. Similarly, a high proportion of Lassa fever and Ebola survivors develop serious long-term symptoms associated with their disease, but virus factors that may determine these complications remain elusive. The central hypothesis of this project, is that specific genetic factors in Lassa and Ebola viruses critically influence infection outcomes. Working directly with unique Lassa and Ebola patient and survivor cohorts in West Africa, we will identify Lassa virus and Ebola virus factors that are determinants of human disease. We will integrate high-throughput ‘omics’ approaches, high-containment experimentation, and computational modeling to elucidate molecular networks that determine infectious disease severity. Based on these findings, we will build predictive models that can be used to determine risk from Lassa virus and Ebola virus infection. We will achieve these goals by completing three overarching goals. In Specific Aim 1, we will create and analyze large-scale genomic data sets of Lassa and Ebola viruses, and genotype of infected patients. We will perform deep investigations of how the viruses evolve as they transmit from their natural reservoirs to humans and between humans, and determine how that can affect clinical outcomes. In Specific Aim 2, we will functionally characterize, in a high-throughput manner, individual Lassa virus and Ebola virus mutations hypothesized to influence infectious outcomes. Finally, in Specific Aim 3 we will perform experiments in high containment to determine functional effects of individual mutations in Lassa virus and Ebola virus, and investigate mechanisms of immune escape and infection. As part of this aim, we will also engineer antibodies to better target both viruses, which can be used as a starting point for future therapeutics.