How does HIV lead to increased susceptibility to tuberculosis?

 描述（由申请方提供）：最近的WHO报告将结核分枝杆菌（Mtb）确定为人类免疫缺陷病毒（HIV）感染个体的单一最大死因，这是一种在撒哈拉以南非洲高度流行的合并感染状态。对结核病感染的易感性似乎比由于CD 4 + T细胞耗竭而失去监测更为复杂。在初步实验中，我们表明，Mtb在巨噬细胞中的复制通过与HIV共感染而增强。我们建议在纽约州伊萨卡的康奈尔大学对实验性合并感染进行广泛的细胞和分子分析。此外，我们在马拉维布兰太尔的伊丽莎白女王中央医院（QECH）有一个艾滋病毒研究队列，并将通过分析艾滋病毒感染者肺部的巨噬细胞和淋巴细胞来探索体外表型的相关性。目前的研究是建立在假设艾滋病毒感染的肺泡巨噬细胞发挥了重要作用，增加易感性的发展活动性结核病。具体目标#1。HIV感染如何促进结核分枝杆菌的细胞内生长？A.是什么导致宿主细胞的宽容性增加？为了阐明HIV感染促进细菌存活的机制，我们针对以下3个问题：Mtb的生长优势仅限于HIV感染的细胞吗？二. HIV感染是否调节巨噬细胞的杀微生物活性？三.什么样的HIV ORF介导了巨噬细胞环境中的这种改变？B。结核分枝杆菌如何利用这种增加的宽容？我们提出了有偏见和无偏见的遗传筛选，以确定增强结核分枝杆菌在HIV感染的HMDM的增长所需的基因。I.基于脂质代谢改变有利于细菌复制的假设的偏见方法。二. HIV感染巨噬细胞中Mtb的无偏转座子插入位点作图（TraSH）筛选。具体目标#2。HIV如何影响肺部的免疫环境，使其更容易感染和/或结核病进展？我们将评估艾滋病毒使AM更容易感染结核分枝杆菌的能力。A.利用HMDM作为开发Mt B存活测定B的替代物。人类肺泡巨噬细胞的功能表型在HIV感染中是如何被调节的？

 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?