This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this study has been to document the early dissemination and pathology of DENGUE virus infection in rhesus macaques. Human infection with Dengue virus is generally detected about one week post infection and there is therefore a dearth of information on the early event of virus infection in a model close to man. Infection of 6 rhesus macaque with a high dose of Dengue serotype 2 intravenously has for the first time induced reproducible albeit generally mild coagulopathies starting on day 3 and lasting to 7-10 days post infection. These coagulopathies have resulted in subcutaneous widely distributed ecchymoses as well as generally disseminated petechia in the most severe cases. The mechanisms in the coagulation cascade that are impaired by Dengue infection in vivo appear to center on protein C and may provide us a novel therapeutic window for fatal human dengue hemorrhagic fever in humans. These studies have allowed us to define the initial targets of Dengue virus which appear to target megakaryocytes and platelets. Finally the role of innate responses and dendritic cells and macrophage in particular can be evaluated during the acute phase of infection in vivo using this model.
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