Mechanism of immune dysregulation secondary to methamphetamine abuse.

描述（由申请人提供）：甲基苯丙胺（METH）滥用会损害宿主的防御机制，并被认为会增强宿主对感染的易感性。甲基苯丙胺滥用者HIV-1感染的高发生率和甲基苯丙胺对免疫系统的潜在影响强调了甲基苯丙胺-HIV-1合发的临床意义。尽管甲基安非他明滥用与免疫失调有关，但甲基安非他明暴露与无法引起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，特别是CD8+T细胞反应，在控制HIV-1感染中起着关键作用。缺乏对甲基苯丙胺滥用对控制HIV-1感染的获得性免疫反应的影响的了解值得未来考虑。我们的初步数据显示，甲基安非他明暴露增加了人原代T细胞的胞质钙水平，导致ROS的产生，这与线粒体损伤和T细胞功能障碍相关。我们发现甲基安非他明暴露改变了调节细胞信号传导、增殖和分化、细胞介导的免疫反应和转录共激活的基因表达，可能导致甲基安非他明介导的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）被甲基安非他明刺激到T细胞上，这意味着甲基安非他明的一些作用可能归因于该受体的活性。通过结合体外（分子、生化和功能分析）和体内慢性病毒感染动物模型（HIV-1脑炎SCID小鼠模型和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)甲基甲醚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)甲基甲醚介导的免疫功能障碍对宿主对慢性病毒感染（HIV-1/LCMV感染）的适应性免疫反应有何影响？我们将鉴定甲基安非他明的线粒体底物，并通过蛋白质组学和分子生物学方法描述参与这些作用的途径。拟议的工作是非常重要的，因为它将有助于理解HIV-1和甲基苯丙胺滥用对适应性免疫的综合影响的潜在机制。基于这些研究的增强T细胞免疫的治疗方法将减少持续感染。

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.