Kinetics and immunology of early Ebola virus infection (PREVIREMIX)

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Ebola virus (EBOV) is the etiological agent of the recent Ebola virus disease (EVD) epidemics in West and Central Africa and has caused outbreaks of severe hemorrhagic fever in Africa for the last 40 years. Human infection from either a zoonotic source of from exposure to other infected humans involves direct contact with infected body fluids and fomites, and therefore, requires initial virus infection of skin and mucosal surfaces. Once, initial infection is established, the virus needs to spread to secondary lymphoid organs and the blood, thereby causing a multiorganic disease. A wealth of data gathered during the recent West African outbreak, indicate that EVD outcome is correlated to a great extent with the ability of the virus to spread systemically and sustain high levels of replication within the host. However, the mechanisms by which EBOV travels from its portals of entry to the blood are entirely unknown. The goal of this proposal is to study the kinetics of EBOV infection and dissemination from the initial sites of infection to the blood. Our model systems will be chimeric and humanized mice retaining wild type murine and human hematopoiesis respectively, human cells and tissues. We will use a multiparametric and integrative approach including Prime Flow RNA assays, multiparamertric flow and mass cytometry and genomics. Major objectives will be to identify early virus target cells and to determine the role of migratory dendritic cells on virus dissemination and T-cell mediated immunity.