Role of cytokines in retroviral neuropathogenesis

描述（由申请人提供）：中枢神经系统逆转录病毒感染可导致严重和衰弱的神经系统疾病。这方面的一个重要例子是人类免疫缺陷病毒（HIV）引起的痴呆，它影响了大约10-20%的HIV感染者。在hiv -痴呆以及SIV脑炎、FIV脑炎和多嗜性小鼠逆转录病毒诱导的神经系统疾病的动物模型中，严重临床疾病的发展与中枢神经系统显著的病理损伤无关。因此，这些逆转录病毒诱导神经系统疾病的机制尚不清楚。几种宿主基因的表达增加，包括促炎细胞因子TNF α和趋化因子MCP-1、MIP-1 α、MIP-1 β和RANTES，已被证明与hiv感染患者以及SIV、FIV和多嗜性小鼠逆转录病毒感染动物模型中的神经系统症状相关。然而，这些基因表达的增加对宿主是有益还是有害尚不清楚。本提案的总体目的是研究促炎细胞因子和趋化因子在逆转录病毒诱导的神经系统疾病中的作用。使用多嗜性逆转录病毒诱导疾病的小鼠模型，我们已经表明，敲除小鼠缺乏TNF α或CCR2 （MCP-1的主要受体）的基因，比野生型对照组更不容易受到逆转录病毒诱导的神经系统疾病的影响。然而，TNF α或CCR2缺陷小鼠对神经毒性多嗜性逆转录病毒Fr98都没有完全抗性。在目前的提案中，我们将通过分析TNFalpha和CCR2双敲除小鼠对fr98诱导的神经系统疾病的易感性，来确定TNF α和MCP-1/CCR2是否是神经系统疾病的主要介质。此外，我们将确定在CNS中TNF α和/或MCP-1的过表达是否可以在感染一种无毒的多性逆转录病毒Fr54时诱导临床症状。最后，通过原位杂交，我们确定TNF α和MCP-1不是由感染的小胶质细胞产生的，而是由未感染的细胞类型（包括神经元和星形胶质细胞）产生的。因此，我们还将分析受感染的小胶质细胞如何在体内调节TNF α和mcp -1的产生。

DESCRIPTION (provided by applicant): Retrovirus infection of the central nervous system can result in severe and debilitating neurological disease. An important example of this is Human Immunodeficiency Virus (HIV)-induced dementia, which affects approximately 10-20% of HIV-infected individuals. In HIV-dementia and in the animal models of SIV encephalitis, FIV encephalitis and polytropic murine retrovirus-induced neurological disease, the development of severe clinical disease is not associated with a remarkable amount of pathological damage in the CNS. Thus, the mechanism by which these retroviruses induce neurological disease is unclear. Increased expression of several host genes, including the proinflammatory cytokine TNF alpha and chemokines MCP-1, MIP-1 alpha, MIP-1 beta, and RANTES, have been shown to correlate with neurological symptoms in HIV-infected patients as well as in the animal models of SIV, FIV and polytropic murine retrovirus infection. However, it is unknown whether the increased expression of these genes is beneficial or detrimental to the host. The overall aim of this proposal is to study the role of proinflammatory cytokines and chemokines in retrovirus-induced neurological disease. Using the murine model of polytropic retrovirus-induced disease, we have shown that knockout mice deficient in the genes for either TNF alpha or CCR2,the primary receptor for MCP-1, are less susceptible to retrovirus-induced neurological disease than wild type controls. However, neither TNF alpha or CCR2 deficient mice were completely resistant to the neurovirulent polytropic retrovirus, Fr98. In the current proposal, we will determine if TNF alpha and MCP-1/CCR2 are the primary mediators of neurological disease by analyzing double knockout mice deficient in both TNFalpha and CCR2 for susceptibility to Fr98-induced neurological disease. Additionally, we will determine if over expression of TNF alpha and/or MCP-1 in the CNS can induce clinical symptoms during infection with an avirulent polytropic retrovirus, Fr54. Finally, using in situ hybridization we determined that TNF alpha and MCP-1 are not produced by infected microglia cells, but rather uninfected cell types including neurons and astrocytes. Therefore, we will also analyze how infected microglia cells regulate TNF alpha and MCP-1production, in vivo.