Macrophages in the pathogenesis of AIDS

巨噬细胞在艾滋病发病机制中的作用

• 批准号: 8263297
• 负责人: Marcelo J Kuroda
• 金额: $ 84.44万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263297
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Address; Affect; Animals; Biology; Bone Marrow; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cell Count; Cell Death; Cell Lineage; Cells; Cercopithecus pygerythrus; Chronic; Data; Defect; Disease; Disease Progression; Endotoxins; Exhibits; Exposure to; Functional disorder; Gastrointestinal tract structure; Goals; HIV; HIV Infections; HIV-1; Homeostasis; Human; Immune system; Immunologic Deficiency Syndromes; Individual; Infection; Link; Longitudinal Studies; Macaca; Maintenance; Mediating; Modeling; Monkeys; Mucosal Immunity; Natural Immunity; Opportunistic Infections; Pathogenesis; Peripheral; Phenotype; Play; Primate Lentiviruses; Reporting; Role; SIV; Site; Staging; Subfamily lentivirinae; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Uncertainty; Viral Load result; Virus Diseases; adaptive immunity; arm; cell injury; cohort; immune activation; loss of function; lymph nodes; macrophage; microbial; monocyte; nonhuman primate; pathogen; response; theories

DESCRIPTION (provided by applicant): Destruction of CD4+ T cells is considered the primary cause of immunodeficiency manifested by opportunistic infections in HIV-1-infected humans as well as in SIV-infected macaques. Subsequently, HIV/SIV-associated chronic immune activation also has emerged as an important explanation for HIV pathogenesis. Although a clearly-defined mechanism about the cause of this general immune activation has yet to be demonstrated, a microbial translocation theory has been proposed whereby breakdown of the mucosal barrier and mucosal immunity is thought to occur after with depletion of CD4 T cells resulting in systemic exposure to mucosal microbial pathogens and their products (e.g. endotoxin). The cause and effect of this theory of pathogenesis, however, has yet to be elucidated, especially since not all infected individuals with low CD4 T cell levels progress similarly to AIDS. The purpose of this proposal is to examine earlier stages of HIV/SIV-associated pathogenesis that could account for microbial translocation by focusing on the role of macrophages. Macrophages are important components of the innate immune system, link the transition from innate to adaptive immunity, and serve as host cell targets of HIV/SIV infection. In support of the rationale to focus on macrophages in this proposal, our recent data showed a high monocyte turnover in SIV-infected animals compared to control uninfected animals that directly correlated with progression to AIDS. Massive destruction of tissue macrophages observed in the lymph nodes of an infected monkey appeared to contribute to a high monocyte turnover rate. Furthermore, preliminary data indicated that a specific cell subset of recently differentiated macrophages from monocytes were the main target of SIV infection. The main goal of the proposed application is to address the role of tissue macrophages in the pathogenesis of AIDS using the non-human primate model of SIV infection. The goal of this proposal is to determine if microbial translocation leading to systemic immune activation is due to faltering innate immunity by dysfunctional macrophages. The hypothesis is that damage to specific macrophage cell subsets by SIV infection will compromise the first line of defense in innate immunity, and as a consequence, the bacterial flora of the digestive tract will break through the mucosal barrier to contribute to systemic immune activation and pathogenesis of AIDS. PUBLIC HEALTH RELEVANCE: Studies to understand the pathogenesis of AIDS in HIV infection have focused primarily on T cells. This is because CD4+T cells are a major target of HIV infection, and the loss of these cells correlates with AIDS. While there is no doubt that CD4+ deficiency plays a major role in the pathogenesis of AIDS, our understanding about the impact of HIV infection on innate immunity in general, and on the biology of monocyte/macrophages in particular, has not progressed at the same pace. We hypothesize that in conjunction with declining levels of CD4+ T cells, HIV also affects monocyte/macrophage lineage cells that may have an even more profound impact on the progression of HIV infection to AIDS. We hypothesize that the loss of the innate barrier function of macrophages occurs despite maintenance of absolute cell numbers (i.e. loss of function rather than cell number). Our studies demonstrated that enormous effort is given by the bone marrow to maintain the needed numbers of circulating monocytes over the course of SIV infection (via high turnover of cells) in response to the massive destruction of tissue macrophages. This observation supports a crucial role of the monocyte/macrophage cell lineage in the maintenance of daily immunological homeostasis. The high turnover rate by the bone marrow to supply and maintain monocyte/macrophages levels during SIV infection could also explain why damage in this arm of the immune system was not previously reported (whereas CD4+ T cell damage was more readily apparent). The main goal of the proposed application is to address the role of tissue macrophages in the pathogenesis of AIDS using the non-human primate model of SIV infection.

描述（由申请人提供）：CD4+ T 细胞的破坏被认为是 HIV-1 感染的人类以及 SIV 感染的猕猴中机会性感染所表现出的免疫缺陷的主要原因。随后，HIV/SIV 相关的慢性免疫激活也成为 HIV 发病机制的重要解释。虽然关于这种一般免疫激活原因的明确机制尚未得到证实，但已经提出了微生物易位理论，认为粘膜屏障和粘膜免疫的破坏是在 CD4 T 细胞耗竭后发生的，导致全身暴露于粘膜微生物病原体及其产物（例如内毒素）。然而，这种发病机制理论的因果关系尚未阐明，特别是因为并非所有 CD4 T 细胞水平较低的感染者的进展都与艾滋病相似。该提案的目的是检查 HIV/SIV 相关发病机制的早期阶段，通过关注巨噬细胞的作用来解释微生物易位。巨噬细胞是先天免疫系统的重要组成部分，连接先天免疫到适应性免疫的转变，并作为 HIV/SIV 感染的宿主细胞靶标。为了支持本提案中关注巨噬细胞的基本原理，我们最近的数据显示，与未感染的对照动物相比，SIV 感染动物的单核细胞周转率较高，这与艾滋病的进展直接相关。在受感染猴子的淋巴结中观察到的组织巨噬细胞的大规模破坏似乎导致了高单核细胞周转率。此外，初步数据表明，最近从单核细胞分化的巨噬细胞的特定细胞亚群是SIV感染的主要目标。 该申请的主要目标是利用 SIV 感染的非人类灵长类动物模型来探讨组织巨噬细胞在 AIDS 发病机制中的作用。该提案的目的是确定导致全身免疫激活的微生物易位是否是由于巨噬细胞功能失调导致的先天免疫减弱所致。该假说认为，SIV感染对特定巨噬细胞亚群的损害将损害先天免疫的第一道防线，因此消化道的菌群将突破粘膜屏障，促进全身免疫激活和艾滋病的发病机制。 公共卫生相关性：了解 HIV 感染中 AIDS 发病机制的研究主要集中在 T 细胞上。这是因为 CD4+T 细胞是 HIV 感染的主要目标，而这些细胞的丧失与艾滋病相关。毫无疑问，CD4+ 缺陷在 AIDS 的发病机制中发挥着重要作用，但我们对 HIV 感染对先天免疫的影响，特别是对单核细胞/巨噬细胞生物学的影响的理解并没有同步进展。我们假设，随着 CD4+ T 细胞水平的下降，HIV 还会影响单核细胞/巨噬细胞谱系细胞，这可能对 HIV 感染发展为 AIDS 产生更深远的影响。我们假设，尽管绝对细胞数量保持不变（即功能丧失而不是细胞数量丧失），但巨噬细胞先天屏障功能的丧失还是发生了。我们的研究表明，在 SIV 感染过程中（通过细胞的高周转），骨髓付出了巨大的努力来维持所需数量的循环单核细胞，以应对组织巨噬细胞的大规模破坏。这一观察结果支持单核细胞/巨噬细胞谱系在维持日常免疫稳态中的关键作用。 SIV 感染期间骨髓供应和维持单核细胞/巨噬细胞水平的高周转率也可以解释为什么之前没有报道免疫系统这一臂的损伤（而 CD4+ T 细胞损伤更容易明显）。该申请的主要目标是利用 SIV 感染的非人类灵长类动物模型来探讨组织巨噬细胞在 AIDS 发病机制中的作用。