Hemorrhagic fever viruses are potential agents of bioterrorism by virtue of their ability to cause fever, bleeding, and death after infection. The development of these symptoms has been found to be related to the release of inflammatory cytokines (including IL-6, IL-8, and TNF-alpha). In most systems that have been well studied, the release of inflammatory cytokines is controlled by pattern recognition proteins like CD 14 and Toll like receptor proteins (such as TLR2, TLR3, and TLR4). Lymphocytic Choriomeningitis Virus (LCMV), an arenavirus which causes disease in both humans and mice, is a model for studying the pathogenesis of hemorrhagic fever viruses. Preliminary studies of LCMV, using human and mouse cells indicate that the release of cytokines initiated by LCMV is controlled by CD 14 and TLR2. Toll like receptors, because of their ability to release inflammatory cytokines have a dual role in the response to pathogens. While the acute release of cytokines may cause symptoms (fever, shock, and bleeding) that may be detrimental to the host, these same cytokines may be important in initiating long term immunity. To study the role of CD14 and TLRs, transfected human cells as well knockout mice and cell lines derived from TLR knockout mice will be used. The specific proteins involved in the generation of the immune response will be defined and variant viruses that do not induce an inflammatory cytokine response will be isolated and characterized for their ability to induce long lasting immunity with or without the addition of adjuvants. The role of TLRs in the development of immunity to LCMV mediated by NK cells, B, T cells and antigen presenting cells will be studied. These studies will lead to insights about the pathogenesis of bioterrorist agents as well as new insights into how to treat and prevent arenavirus induced disease.
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