The Eastern Province of Sierra Leone has the world?s highest incidence of Lassa fever. Members of this researchteamhavebeenworkingonLassafeverattheKenemaGovernmentHospital(KGH)forovertwelve years. The 2013-16 West African Ebola epidemic began less than a four-hourdrivefromKGHandwasthe ?rst 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 surroundingdistrictsexperiencedalargenumberofEbolacase.Wewillleverageexistingsamplesfromthese established cohorts of humans infected with Lassa fever or Ebola. While it is well established that asymptomaticormildlysymptomaticinfectionsoccurinbothLassafeverandEbola,itisunknownwhichhost 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 Ebolasurvivorgroups. We propose to integrate experimental approaches and computational modeling to test and validate hypothesesofsigni?cancetoLassafeverandEbola.Ourassembledteamhasatrackrecordofcollaboration, uniqueexpertisewithbothLassavirusandEbolavirusandtheappropriatemultidisciplinaryrepresentationin systems and computational biology, virology, immunology, genomics, proteomics, machine learning, statisticalmethodsandmodelingrequiredtoexecutetheproposedprogram.OuroverallgoalinProject1isto generateanintegrateddatasetthatcanbeusedtobuildpredictivemodelsofpatientoutcomesinLassafever and Ebola. Studies proposed underSpeci?cAim1willde?nephysiologicalattributesthatdistinguishLassa fever and Ebola survivors and non-survivors, and individuals that develop serioussequelae.Speci?cAim2 willelucidatetheevolutionandfunctionofsuccessfulantibodynetworksinEbolaandLassafeversurvivors.T cell dynamics and the role human leukocyte antigens leading to successful clearance of Ebola virus and Lassaviruswillbede?nedinstudiesdescribedinSpeci?cAim3.InSpeci?cAim4wewilldevelopandtest predictive models for the role of host factors in Lassa fever and Ebola outcome. Project 1 on hostfactors complements the studies described in Project 2onviralfactorsandintegrateswithandutilizeseachofthe Cores.
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