Mechanism of immune dysregulation secondary to methamphetamine abuse.

描述(申请人提供)：甲基苯丙胺(冰毒)滥用损害宿主防御机制，并被认为增加宿主对感染的易感性。冰毒滥用者中艾滋病毒-1感染的高发病率以及冰毒对免疫系统的潜在影响突出了冰毒-艾滋病毒-1共同发病的临床意义。尽管滥用冰毒与免疫调节失调有关，但冰毒暴露与无法引发保护性适应性免疫反应之间的因果关系仍然难以捉摸。获得性免疫，尤其是CD8 T细胞应答，在控制HIV-1感染中起着关键作用。在控制HIV-1感染的过程中，对滥用冰毒对获得性免疫反应的影响缺乏了解，这是今后需要考虑的问题。我们的初步数据显示，冰毒暴露增加了原代人类T细胞的胞浆钙水平，导致了与线粒体损伤和T细胞功能障碍相关的ROS的产生。我们发现，冰毒暴露改变了调控细胞信号、增殖和分化的基因表达，细胞介导的免疫反应和转录共激活可能导致冰毒介导的T细胞功能障碍。我们首次发现，微量胺相关受体(TAAR1，一种被胺激活的新型受体)可被冰毒刺激T细胞，暗示某些冰毒效应可能与该受体的活性有关。利用体外(分子、生化和功能分析)和体内慢性病毒感染动物模型(SCID小鼠HIV-1脑炎模型和LCMV小鼠模型)长期暴露于冰毒，我们将解决以下问题：(1)冰毒对T细胞线粒体动力学的病理生理影响是什么？(2)冰毒介导的线粒体功能障碍对T细胞的潜在机制和分子后果是什么，它们在细胞免疫细胞损伤中起什么作用？(3)冰毒介导的免疫功能障碍对慢性病毒感染(HIV-1/LCMV感染)的宿主适应性免疫反应有什么影响？我们将利用蛋白质组学和分子生物学方法鉴定冰毒的线粒体底物，并描述参与这些作用的途径。拟议的工作具有非常重要的意义，因为它将有助于理解艾滋病毒-1和冰毒滥用对适应性免疫的综合影响的潜在机制。基于这些研究的提高T细胞免疫的治疗方法将减少持续性感染。 与公共健康相关：甲基苯丙胺，一种高度上瘾的兴奋剂，被数百万美国人滥用，众所周知会改变免疫功能，增加感染的易感性。流行病学研究表明，越来越多的证据表明，滥用冰毒与艾滋病毒-1感染发病率增加之间存在联系。然而，滥用冰毒与艾滋病毒-1感染的易感性或其进展之间的明显因果关系在很大程度上是未知的。目前的建议旨在了解在滥用冰毒和艾滋病毒-1感染的背景下免疫功能障碍的假定机制。

DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse impairs host defense mechanisms and is thought to enhance host susceptibility to infections. High incidence of HIV-1 infection in METH abusers and potential effects of METH on the immune system underscore the clinical significance of METH-HIV-1 co-morbidity. Although METH abuse is implicated in dysregulation of immunity, the causal interrelationship between METH exposure and the inability to elicit protective adaptive immune response remains elusive. Acquired immunity, in particular CD8+T cell response, plays a pivotal role in control of HIV-1 infection. Lack of understanding of impact of METH abuse on acquired immune response in controlling HIV-1 infection warrants future considerations. Our preliminary data showed that METH exposure increased cytosolic calcium levels in primary human T cells leading to generation of ROS that correlated with mitochondrial injury and T cell dysfunction. We found that METH exposure altered gene expression regulating cell signaling, proliferation and differentiation, cell-mediated immune responses and transcriptional co-activation potentially contributing to METH-mediated T cell dysfunction. For the first time, we showed that trace amine associated receptor (TAAR1, a novel receptor activated by amines) is stimulated by METH on T cells implying that some of METH effects may be attributable to activity of this receptor. Using a combination of in vitro (molecular, biochemical and functional assays) and in vivo animal models of chronic viral infection (SCID mouse model for HIV-1 encephalitis and LCMV mouse model) chronically exposed to METH, we will address the following questions: (1) What are the pathophysiological effects of METH on T cell mitochondrial dynamics? (2) What are the underlying mechanisms and molecular consequences of METH-mediated mitochondrial dysfunction on T cells and what roles do they play in cell immune cell impairment? (3) What effects does METH-mediated immune dysfunction have on the host adaptive immune responses to chronic viral infections (HIV-1/LCMV infection)? We will identify mitochondrial substrates of METH and delineate pathways involved in these effects by using proteomic and molecular biological approaches. The proposed work is highly significant, as it will contribute to understanding of the underlying mechanisms of the combined effects of HIV-1 and METH abuse on adaptive immunity. Therapeutic approaches towards boosting T cell immunity based on these investigations will reduce persistent infection. PUBLIC HEALTH RELEVANCE: Methamphetamine, a highly addictive stimulant abused by millions of Americans and is known to alter immune function and increase susceptibility to infection. Epidemiological studies indicate growing evidence of the association between METH abuse and an increased incidence of HIV-1 infections. However, the apparent causal interrelationship between METH abuse and susceptibility to HIV-1 infection or its progression are largely unknown. Current proposal aims to understand putative mechanisms of immune dysfunctions in the setting of METH abuse and HIV-1 infection.