This project will examine the role of the innate immune system in the pathophysiology of the viralhemorrhagic fevers. Two viruses which are potential agents of bioterrorism, will be studied: 1) Ebola virus, afilovirus, which induces an acute illness characterized by fever, leucopenia, shock, and death, and 2)Lymphocytic Choriomeningitis Virus LCMV an arenavirus which causes an illness characterized byleucopenia and thrombocytopenia in mice and meningitis in humans. The high mortality rate associated withEbola infection has-been demonstrated to be directly associated with cytokine release which occurs after viralinfection of macrophages. The mechanism by which Ebola induces this cytokine response will be defined andcompounds will be screened for their ability to inhibit this activity. Preliminary data indicate a major role forToll Like Receptor 2 (TLR-2) and CD14 in the cytokine response to LCMV. TLR-2 and CD14 are patternrecognition proteins whose role in bacterial sepsis has been recently defined. Both have also been associatedwith the immune responses to viruses. Using transfected cell lines and available knockout mice themechanism by which these proteins affect both initial induction of cytokines as well as the subsequentimmune responses to LCMV and Ebola virus will be defined. The specific TLRs (and other 'patternrecognition proteins') involved in these responses as well as their interactions will be studied. The effect ofthese early recognition events on long-term Band T cell immunity will be investigated. These studies willresult in a better understanding of the role that the innate immune system has in mediating thepathophysiology of hemorrhagic fever viruses and should lead to new therapeutic approaches to thesediseases.
Showing the most recent 10 out of 417 publications
