Opioid, Astroglial TLR3/RIG-I Signaling and HIV

描述（申请人提供）：星形胶质细胞是中枢神经系统（CNS）中最丰富的胶质细胞群，在中枢神经系统炎症反应中起重要作用。然而，越来越多的证据表明星形胶质细胞参与中枢神经系统的先天免疫，因为它们展示了一系列参与先天免疫的受体。星形胶质细胞表达toll样受体（TLR）家族的某些成员，特别是TLR3，它是对病毒感染的先天免疫反应的主要触发因子。此外，星形胶质细胞功能表达视黄酸诱导基因i (RIG-I)，这是抗病毒免疫的关键介质。我们的早期研究表明，星形胶质细胞中TLR3的激活抑制了HSV的复制。我们还发现巨噬细胞的TLR3信号抑制HIV复制。然而，星形胶质细胞的TLR3/ rig - 1信号在抗HIV的神经保护和中枢神经系统先天免疫中的作用尚不清楚。此外，关于阿片类药物是否会损害星形胶质细胞的抗病毒功能的信息也很少。本项目的总体目的是确定TLR3和RIG-I激活星形胶质细胞的抗hiv活性和神经保护作用，以及阿片类药物对星形胶质细胞TLR3/RIG-I信号传导的影响。我们假设星形胶质细胞TLR3/ rig - 1信号可以对HIV产生有效的免疫并保护神经元细胞。此外，我们假设吗啡损害星形胶质细胞介导的抗病毒免疫并促进小胶质细胞的HIV感染。我们提出了两个具体的目标来解决这些假设：目的1确定星形胶质细胞TLR3/ rig - 1信号对小胶质细胞HIV感染的影响（胶质-胶质相互作用）以及吗啡对这种星形胶质细胞介导的抗HIV作用的影响。目的2：确定星形胶质细胞TLR3/ rig - 1信号在吗啡使用和/或HIV背景下对神经元细胞保护的影响。这些研究将首次揭示星形胶质细胞TLR3/RIG- I信号在神经元细胞保护和中枢神经系统抗HIV先天免疫中的有益作用。

DESCRIPTION (provided by applicant): As the most abundant glial cells population within the central nervous system (CNS), astrocytes play an important role in the CNS inflammatory reactions. However, there is emerging evidence that astrocytes participate in the CNS innate immunity, as they display an array of receptors involved in innate immunity. Astrocytes express certain members of the Toll-like receptors (TLR) family, in particular, TLR3, a major trigger of innate immune response to viral infections. In addition, astrocytes functionally express retinoic acid-inducible gene-I (RIG-I), a key mediator of antiviral immunity. Our early studies demonstrated that the activation of TLR3 in astrocytes inhibited HSV replication. We also showed that TLR3 signaling of macrophages suppress HIV replication. However, it is unclear about the role of TLR3/RIG-I signaling of astrocytes in the neuroprotection and CNS innate immunity against HIV. Also, there is little information about whether opioids impair the antiviral function of astrocytes. The overall aim of this project is to determine the anti-HIV activity and neuroprotective effect of TLR3 and RIG-I activation of astrocytes and the impact of opioids on astroglial TLR3/RIG-I signaling. We hypothesize that the astroglial TLR3/RIG-I signaling can mount an effective immunity against HIV and protect neuronal cells. Furthermore, we hypothesize that morphine compromises astrocyte-mediated antiviral immunity and facilitates HIV infection of microglia. We propose two specific aims to address these hypotheses: Aim 1 Determine the effect of astroglial TLR3/RIG-I signaling on HIV infection of microglia (glia-glia interaction) and the impact of morphine on this astrocyte-mediated anti-HIV action. Aim 2 Determine the effect of astroglial TLR3/RIG-I signaling on the neuronal cell protection in the context of morphine use and/or HIV. These proposed studies should for the first time provide insight of the beneficial role of astroglia TLR3/RIG- I signaling in the neuronal cell protection ad the CNS innate immunity against HIV.