Virus-induced inflammatory diseases, including arthritis, pneumonia, and encephalitis, are a significant cause of human disease, and there is a clear need to improve our overall understanding of the pathogenesis of this diverse array of conditions. Togaviruses, which include the mosquito-borne alphaviruses such as Chikungunya, O'nyong-nyong, and Ross River virus cause massive outbreaks of infectious arthritis/athralgia/myalgia affected thousands to millions of individuals and continue to be an emerging threat. However, even though these viruses can cause severe rheumatic disease on a massive scale, relatively little is known about their pathogenesis. We and others have developed a mouse model of RRV-induced arthritis and myositis, where the virus replicates to high levels in the synovial joints and skeletal muscle, but virus induced disease is dependent on an immunopathologic inflammatory response largely comprised of macrophages. Studies on the host factors that regulate this response demonstrated that activation of the host complement cascade is required for the development of virus-induced tissue destruction, but not recruitment of inflammatory cells into the virus-infected tissues. Therefore, the objectives of this proposal are to investigate the role that complement plays in the pathogenesis of RRV- induced disease, including analysis of the mechanisms by which RRV infection activates the complement system and the downstream functions of complement in regulating the immunopathologic inflammatory response. We also propose to extend these studies from the mouse model back to the human disease in order to determine whether complement activation is a component of the virus-induced inflammatory response in individuals suffering from alphavirus-induced arthritis. Therefore, this work will significantly enhance our understanding of the pathogenesis of Togavirus-induced arthritis/myalgia, while also providing insights into novel viral interactions with the host complement cascade and inflammatory response that may ultimately lead to better understanding of the mechanisms that regulate other pathologic virus-induced inflammatory responses, such as occur in viral arthritis, encephalitis, or pneumonia.
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