HIV-induced Defects in Pulmonary Macrophages Exacerbate Mycobacterium Tuberculosis Co-infection

摘要 结核病是艾滋病毒感染者死亡的主要原因。结核病风险增加 在CD 4 + T细胞耗竭之前，并可在抗逆转录病毒（ARV）恢复T细胞后继续 疗法由于两个个体的侵袭性过程，合并感染者的治疗具有挑战性 疾病;临床问题，进一步复杂化的药物相互作用和吸收不良的问题， 联合抗逆转录病毒药物和结核病化疗。应对这些临床挑战需要更大的 了解共同感染的病理生理学。在该领域出现了严重的知识差距， 支持HIV复制的动物模型有限。为了解决这个问题，我们开发了一种新的 BLT人源化小鼠（HuMouse）中的TB/HIV模型，该模型再现了重要的病理和 人类疾病的免疫学特征。通过使用我们独特的动物模型，我们现在能够研究 肺中HIV-1和结核分枝杆菌（Mtb）感染的微生物协同作用。因此，我们有 确定了肺巨噬细胞（M β）共感染协同作用的候选分子机制， 促炎环境和增加分枝杆菌增殖。本R 01应用程序的目的是 使用结核病/艾滋病病毒联合感染的新HuMouse模型，进一步阐明艾滋病病毒 感染破坏肺结核对Mtb的先天免疫应答。我们的假设是 HIV-1感染引起的肺巨噬细胞中IL-1 β的炎性小体依赖性激活， 对Mtb的炎症反应过度，进而产生嗜肺菌介导的肺损伤， 组织坏死增加。我们有两个目的来检验以下个人假设：1）艾滋病毒和结核病 共感染通过炎症体依赖性激活宿主中IL-1 β驱动促炎性肺环境 M），和2）由于共感染的促炎环境导致的Th 17细胞偏好的发展， IL-17依赖性中性粒细胞募集和肺损伤。这些目标将通过使用 用Mtb/HIV共感染的人源化小鼠进行的体内研究和用分离的肺支原体进行的体外机制研究。 我们工作的预期成果是在我们理解艾滋病毒如何操纵免疫系统方面取得重大进展。 宿主对Mtb炎症反应促进侵袭性疾病。这些结果的积极影响将是 确定新的靶点，进行临床干预，以恢复正常的宿主免疫力，减少疾病， 数百万艾滋病毒感染者。

Abstract Tuberculosis (TB) is the leading cause of death in people living with HIV infection. An increased risk of TB precedes CD4+ T cell depletion and can continue following restoration of T cells by anti-retroviral (ARV) therapy. Treatment of co-infected persons is challenging due to the aggressive course of both individual diseases; a clinical problem that is further complicated by drug interaction and malabsorption issues when combining ARVs and TB chemotherapy. Addressing these clinical challenges requires a much greater understanding of co-infection pathophysiology. A critical knowledge gap has developed in the field due to the limited availability of animal models that support HIV replication. To address this gap we developed a novel model of TB/HIV in the BLT humanized mouse (HuMouse) that reproduces important pathological and immunological features of human disease. By using our unique animal model, we are now able to study the microbial synergy of HIV-1 and Mycobacterium tuberculosis (Mtb) infection in the lung. As a result, we have identified candidate molecular mechanisms for co-infection synergy in lung macrophages (M) that promote a pro-inflammatory environment and increase mycobacterial proliferation. The objective of this R01 application is to use the new HuMouse model of TB/HIV co-infection to further elucidate the mechanisms whereby HIV infection disrupts the innate immune response of pulmonary M to Mtb. Our hypothesis is that inflammasome-dependent activation of IL-1 in pulmonary M due to HIV-1 infection drives a hyperinflammatory response to Mtb, which in turn produces neutrophil-mediated lung damage and increased tissue necrosis. We have two aims to test the following individual hypotheses that 1) HIV and Mtb co-infection drive a pro-inflammatory lung environment via inflammasome-dependent activation of IL-1 in host M, and 2) development of a Th17 cell bias due to the pro-inflammatory environment of co-infection leads to IL-17-dependent neutrophil recruitment and damage in the lungs. These aims will be accomplished by using in vivo studies with Mtb/HIV co-infected humanized mice and in vitro mechanistic studies with isolated lung M. The expected outcome of our work is a significant advance in our understanding of how HIV manipulates the host inflammatory response to Mtb to promote aggressive disease. The positive impact of these results will be identification of new targets to intervene clinically to restore normal host immunity and reduce disease in millions of HIV-infected people.