How does HIV lead to increased susceptibility to tuberculosis?

艾滋病毒如何导致结核病易感性增加？

基本信息

批准号：
9281672
负责人：
DAVID G RUSSELL
金额：
$ 54.66万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9281672
关键词：
Acquired Immunodeficiency Syndrome Africa South of the Sahara Alveolar Macrophages Apoptosis Area Bacteria Bacterial Genes Behavior Biogenesis Biological Assay Biology CD4 Positive T Lymphocytes Cause of Death Cell Culture Techniques Cells Clinical Research Cohort Studies Complex Containment Defect Development Disease Environment Foamy Macrophage Genes Genetic Screening Growth HIV HIV Infections HIV Seropositivity Highly Active Antiretroviral Therapy Hospitals Human Immune Immunocompetence In Vitro Individual Infection Lead Lipids Lung Lymphocyte Macrophage Activation Malawi Mediating Messenger RNA Meta-Analysis Modeling Molecular Analysis Mycobacterium tuberculosis Nutrient Open Reading Frames Phagocytes Phagosomes Phenotype Physiology Play Predisposition Reporter Reporting Risk Risk Factors Role Running Site Stress T-Lymphocyte Translating Tuberculosis Universities Vaccinated Viral Virus Work base co-infection cytokine cytotoxicity experimental analysis experimental study flu genetic approach immune function killings lipid metabolism macrophage microbicide monocyte mutant paracrine permissiveness programs public health relevance reconstitution tissue culture

项目摘要

DESCRIPTION (provided by applicant): Recent WHO reports identify Mycobacterium tuberculosis (Mtb) as the single largest cause of death of individuals infected with the Human Immunodeficiency Virus (HIV), a co-infection state highly prevalent in Sub- Saharan Africa. Susceptibility to TB infection appears to be more complex than loss of surveillance through depletion of CD4+ T-cells. In preliminary experiments we show that replication of Mtb in macrophages is enhanced by co-infection with HIV. We propose extensive cellular and molecular analyses of experimental co- infections to be performed at Cornell University, Ithaca, NY. In addition, we have an HIV study cohort at the Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi and will probe the relevance of in vitro phenotypes through analysis of macrophages and lymphocytes from the lungs of HIV-infected individuals. This current study is founded on the hypothesis HIV infection of alveolar macrophages plays a significant role in the increased susceptibility to development of active tuberculosis. Specific Aim #1. How does HIV infection promote the intracellular growth of Mtb? A. What causes the increased permissiveness of the host cell? To elucidate the mechanism(s) by which HIV infection promotes bacterial survival we are targeting the following 3 questions: i. Is the Mtb growth advantage restricted to HIV infected cells? ii. Does HIV infection modulate the microbicidal activities of the macrophage? iii. What HIV ORFs mediate this alteration in the macrophage environment? B. How does Mtb exploit this increased permissiveness? We propose both biased and unbiased genetic screens to identify genes required for enhanced Mtb growth in HIV-infected HMDM. i. Biased approach based on the hypothesis that the altered lipid metabolism favors bacterial replication. ii. Unbiased Transposon-insertion site mapping (TraSH) screen of Mtb in HIV-infected macrophages. Specific Aim #2. How does HIV impact the immune environment of the lung to render it more permissive to infection and/or progression of tuberculosis? We will assess the capacity of HIV to render AM more permissive to infection by Mtb. A. Utilization of HMDMs as surrogates for the development of a Mtb survival assay B. How is the functional phenotype of human alveolar macrophage modulated in the context of HIV infection?

描述（由申请人提供）：世界卫生组织最近的报告指出，结核分枝杆菌（Mtb）是人类免疫缺陷病毒（HIV）感染者的最大单一死因，这是撒哈拉以南非洲地区高度流行的一种混合感染状态。结核病感染似乎比 CD4+ T 细胞耗竭导致的监测丧失更为复杂。在初步实验中，我们表明结核分枝杆菌在体内复制。我们建议在纽约州伊萨卡康奈尔大学进行广泛的实验性感染的细胞和分子分析。此外，我们在伊丽莎白女王中心医院 (QECH) 设有一个 HIV 研究队列。）在马拉维布兰太尔，将通过分析 HIV 感染者肺部的巨噬细胞和淋巴细胞来探讨体外表型的相关性。目前的研究基于 HIV 感染肺泡巨噬细胞发挥作用的假设。具体目标#1. HIV 感染如何促进 Mtb 的细胞内生长？ A. 是什么导致宿主细胞的许可性增加？感染促进细菌存活我们针对以下 3 个问题： i. Mtb 生长优势是否仅限于 HIV 感染细胞？ iii. 哪些 HIV ORF 介导了巨噬细胞环境中的这种变化？ B. Mtb 如何利用这种增加的许可性？假设改变的脂质代谢有利于 HIV 感染者的细菌复制。具体目标 #2. HIV 如何影响肺部的免疫环境，使其更容易感染结核病和/或进展？利用 HMDM 作为开发 Mtb 存活测定的替代品 B. 在 HIV 感染的情况下，人肺泡巨噬细胞的功能表型是如何调节的？