Modulation of T cell Responses by Ebola Glycoprotein

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DESCRIPTION (provided by applicant): Ebola virus is an emerging human pathogen responsible for outbreaks of severe hemorrhagic fever with mortality rates approaching 90% and represents a potential threat as a bio-terrorism agent. A prominent feature of Ebola virus infection is the lack of an effective immune response, characterized by lymphocyte depletion, suppression of T cell proliferation and little leukocyte infiltration into the sites of infection. The glycoprotein (GP) of Ebola virus has been implicated in causing immunosuppression, although its precise role and the mechanism remain largely unknown. We have recently demonstrated that EBO GP binds to DC-SIGN on the cell surface, leading to enhanced virus attachment and infection of host cells. In addition to the envelope GP, Ebola virus produces a soluble form of glycoprotein (sGP), which also binds to DC-SIGN. Since sGP is not associated with virions, it is unlikely to serve as an attachment factor, and the significance of its binding to the DC surface lectin molecule (DC-SIGN) is not known. DC-SIGN is highly expressed in DCs, which are the most efficient antigen presenting cells for activating naive T cells. DCs are capable of acquiring foreign antigens in the periphery and then trafficking to the secondary lymphoid organs where they present antigens to T cells in the context of major histocompatibility complex (MHC) and multiple co-stimulatory signals. The DC-SIGN molecule plays a role in both processes: 1) it interacts with intercellular adhesion molecule (ICAM)-2 on endothelial cells to facilitate the trafficking of DCs and 2) it interacts with ICAM-3 on T cells to initiate the formation of immunological synapses between DCs and T cells. We hypothesize that Ebola virus sGP, like antibodies to DC-SIGN, may block DC-SIGN interactions with ICAM-2 and/or ICAM-3, thus interfering with the ability of DCs to activate T cells. We will test our hypothesis in an in vitro system to determine whether Ebola virus sGP affects the activation of human T cells by DC-SIGN positive DCs. We will then extend our analysis to the murine model to examine whether Ebola virus glycoprotein interferes with the trafficking of DCs to the secondary lymphoid organs and inhibits the ability of DCs to prime naive antigen-specific T cells in vivo. These results will tell us whether Ebola virus sGP, which is made in abundance, yet has no known function, serves to inhibit T cell activation and thus is partly responsible for the many malfunctions described in immune responses to Ebola virus infection.