Role of cytokines in retroviral neuropathogenesis

细胞因子在逆转录病毒神经发病机制中的作用

• 批准号: 6922805
• 负责人: Karin E Peterson
• 金额: $ 10.8万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922805
• 关键词: Retroviridae; Retroviridae disease; central nervous system; chemokine receptor; cytokine; cytokine receptors; gene expression; genetic regulation; in situ hybridization; laboratory mouse; microarray technology; microglia; monocyte chemoattractant protein 1; nervous system infection; neuropathology; nucleic acid probes; polymerase chain reaction; tissue /cell culture; tumor necrosis factor alpha

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.

描述（由申请方提供）：中枢神经系统的逆转录病毒感染可导致严重和使人衰弱的神经系统疾病。其中一个重要的例子是人类免疫缺陷病毒（HIV）引起的痴呆症，它影响了大约10-20%的HIV感染者。在HIV痴呆和SIV脑炎、FIV脑炎和多变性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CNS中显著量的病理损伤无关。因此，这些逆转录病毒诱导神经系统疾病的机制尚不清楚。已显示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，与HIV感染患者以及SIV、FIV和多嗜性鼠逆转录病毒感染的动物模型中的神经症状相关。然而，目前还不清楚这些基因的表达增加是否对宿主有益或有害。本提案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。使用多变性逆转录病毒诱导疾病的小鼠模型，我们已经表明，TNF α或CCR 2（MCP-1的主要受体）基因缺陷的敲除小鼠对逆转录病毒诱导的神经系统疾病的敏感性低于野生型对照。然而，无论是TNF α或CCR 2缺陷小鼠是完全耐神经毒性多效性逆转录病毒，Fr 98。在目前的提议中，我们将通过分析TNF α和CCR 2缺陷的双基因敲除小鼠对Fr 98诱导的神经系统疾病的易感性来确定TNF α和MCP-1/CCR 2是否是神经系统疾病的主要介质。此外，我们将确定在用无毒的嗜多性逆转录病毒Fr 54感染期间，CNS中TNF α和/或MCP-1的过度表达是否会诱导临床症状。最后，使用原位杂交，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，我们也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。