Role of cytokines in retroviral neuropathogenesis

描述(由申请人提供)：逆转录病毒感染中枢神经系统可导致严重和衰弱的神经系统疾病。一个重要的例子是人类免疫缺陷病毒(HIV)引起的痴呆症，它影响到大约10%-20%的艾滋病毒感染者。在HIV痴呆和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，严重临床疾病的发生与中枢神经系统显著的病理损害无关。因此，这些逆转录病毒引发神经系统疾病的机制尚不清楚。一些宿主基因的表达增加，包括促炎细胞因子TNFα和趋化因子MCP-1、MIP-1α、MIP-1β和RANTES，已被证明与HIV感染患者的神经系统症状以及SIV、FIV和多嗜鼠逆转录病毒感染的动物模型相关。然而，目前尚不清楚这些基因的表达增加对宿主是有利还是不利。这项建议的总体目标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。利用多向逆转录病毒诱导的小鼠疾病模型，我们已经证明，缺乏肿瘤坏死因子α或CCR2(MCP-1的主要受体)基因的敲除小鼠比野生型对照小鼠更不容易患逆转录病毒诱导的神经系统疾病。然而，无论是肿瘤坏死因子α还是CCR2缺陷的小鼠，都不能完全抵抗神经毒力多嗜性逆转录病毒Fr98。在目前的方案中，我们将通过分析双基因敲除小鼠对Fr98诱导的神经系统疾病的易感性，来确定肿瘤坏死因子α和MCP-1/CCR2是否是神经疾病的主要介质。此外，我们将确定在中枢神经系统过度表达肿瘤坏死因子α和/或单核细胞趋化蛋白-1是否会在感染强毒多嗜性逆转录病毒Fr54期间引起临床症状。最后，通过原位杂交，我们确定了肿瘤坏死因子α和单核细胞趋化蛋白-1不是由感染的小胶质细胞产生的，而是包括神经元和星形胶质细胞在内的未感染的细胞类型。因此，我们还将分析感染的小胶质细胞如何在体内调节肿瘤坏死因子α和单核细胞趋化蛋白-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.