Macrophages in the pathogenesis of AIDS

巨噬细胞在艾滋病发病机制中的作用

基本信息

批准号：
8963419
负责人：
Marcelo J Kuroda
金额：
$ 78.85万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8963419
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

项目摘要

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.

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的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 细胞耗尽后发生的，导致全身性免疫反应。接触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阐明组织巨噬细胞在 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功能失调的巨噬细胞导致先天免疫减弱所致。假设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发病机制艾滋病。