Pathogenesis of alphavirus-induced arthritis in mice.

描述（由申请方提供）：甲病毒，如鸡胚病毒和罗斯河病毒（RRV），是世界范围内的重要致病原因。 虽然甲病毒引起的关节炎的发病机制知之甚少，但病毒与先天免疫系统的相互作用可能导致疾病。 因此，我们建议在RRV诱导的炎症小鼠模型中表征先天性炎症介质（如细胞因子、趋化因子和模式识别受体）的作用。 我们提出以下具体目标。 1)在体内和体外表征炎性细胞因子和趋化因子对RRV感染的反应。 2)确定IFN-γ在RRV诱导的疾病中的作用。 与野生型小鼠不同，IFN-γ缺陷型小鼠不会发生严重的疾病，将用于研究IFN-γ在RRV发病机制中的作用。 将研究RRV感染小鼠中IFN-γ的细胞来源。 3)研究模式识别受体在RRV诱导的炎症和免疫反应中的作用。 Toll样受体和含CARD的RNA解旋酶RIG-1将使用转染系统和RNAi技术评估其在体外识别罗斯河病毒感染中的作用。 进一步的研究将阐明引起炎症反应的病毒成分。

DESCRIPTION (provided by applicant): Alphaviruses, such as Chickungunya and Ross River virus (RRV), are a significant cause of disease worldwide. Though the pathogenesis of alphavirus-induced arthritides is poorly understood, viral interactions with the innate immune system likely contribute to disease. Therefore, we propose to characterize the role of innate inflammatory mediators, such as cytokines, chemokines, and pattern recognition receptors, in a mouse model of RRV-induced inflammation. We propose the following specific aims. 1) Characterize the inflammatory cytokine and chemokine response to RRV infection in vivo and in vitro. 2) Determine the role of IFN-gamma in RRV-induced disease. IFN-y-deficient mice, which unlike wild-type mice do not develop severe disease, will be used to investigate IFN-gamma's role in RRV pathogenesis. Cellular sources of IFN-gamma in RRV-infected mice will be investigated. 3) Investigate the role of pattern recognition receptors in RRV-induced inflammatory and immune responses. Toll-like receptors and the CARD-containing RNA helicase RIG-1 will be evaluated for their role in recognizing Ross River virus infection in vitro using transfection systems and RNAi technology. Additional studies will elucidate viral components that elicit inflammatory responses.