Project Summary / Abstract The Eastern Province of Sierra Leone has the world’s highest incidence of Lassa fever. Members of this research team have been working on Lassa fever at the Kenema Government Hospital (KGH) for over twelve years. The 2013-16 West African Ebola epidemic began less than a four-hour drive from KGH and was the first Ebola outbreak to occur in an area close to an existing facility for viral hemorrhagic fever basic and clinical research. KGH manages up to 600 suspected Lassa fever patients per year, and Kenema and surrounding districts experienced a large number of Ebola case. We will leverage existing samples from these established cohorts of humans infected with Lassa fever or Ebola. While it is well established that asymptomatic or mildly symptomatic infections occur in both Lassa fever and Ebola, it is unknown which host factors determine the progression to fulminant hemorrhagic fever. Likewise, a substantial portion of Lassa fever and Ebola survivors develop a plethora of serious sequelae, but factors that predicate these complications remain elusive. Our research program supports both Lassa fever and Ebola survivor groups. We propose to integrate experimental approaches and computational modeling to test and validate hypotheses of significance to Lassa fever and Ebola. Our assembled team has a track record of collaboration, unique expertise with both Lassa virus and Ebola virus and the appropriate multidisciplinary representation in systems and computational biology, virology, immunology, genomics, proteomics, machine learning, statistical methods and modeling required to execute the proposed program. Our overall goal in Project 1 is to generate an integrated dataset that can be used to build predictive models of patient outcomes in Lassa fever and Ebola. Studies proposed under Specific Aim 1 will define physiological attributes that distinguish Lassa fever and Ebola survivors and non-survivors, and individuals that develop serious sequelae. Specific Aim 2 will elucidate the evolution and function of successful antibody networks in Ebola and Lassa fever survivors. T cell dynamics and the role human leukocyte antigens leading to successful clearance of Ebola virus and Lassa virus will be defined in studies described in Specific Aim 3. In Specific Aim 4 we will develop and test predictive models for the role of host factors in Lassa fever and Ebola outcome. Project 1 on host factors complements the studies described in Project 2 on viral factors and integrates with and utilizes each of the Cores.