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

摘要 结核病(TB)是艾滋病毒感染者死亡的主要原因。患结核病的风险增加 在CD4+T细胞耗尽之前，并可在抗逆转录病毒(ARV)恢复T细胞后继续 心理治疗。由于两人的侵袭性病程，对合并感染者的治疗具有挑战性。 疾病；因药物相互作用和吸收不良问题而进一步复杂化的临床问题 将抗逆转录病毒药物和结核病化疗结合起来。解决这些临床挑战需要更大的 了解混合感染的病理生理学。由于以下原因，该领域出现了严重的知识差距 支持艾滋病毒复制的动物模型的可获得性有限。为了解决这一差距，我们开发了一部小说 在BLT人源化小鼠(HuMouse)中复制重要病理和免疫缺陷病毒的TB/HIV模型 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 HIV-1和结核分枝杆菌(Mtb)在肺部感染的微生物协同作用。因此，我们有 肺巨噬细胞(M-)合并感染协同作用的候选分子机制 促进炎症环境，增加分枝杆菌增殖。此R01应用程序的目标是 是使用新的结核/艾滋病毒混合感染的HuMouse模型来进一步阐明HIV 感染扰乱了肺M对结核分枝杆菌的天然免疫应答。我们的假设是 HIV-1感染引起的IL-1在肺M中的炎症性激活 对结核分枝杆菌的高炎症反应，进而产生中性粒细胞介导的肺损伤和 组织坏死率增加。我们有两个目标来检验以下个人假设：1)艾滋病毒和结核分枝杆菌 混合感染通过炎症体依赖的宿主IL-1的激活来驱动促炎的肺环境 2)由于混合感染的促炎环境而导致的Th17细胞偏向的发展导致 IL-17依赖的中性粒细胞在肺部的募集和损伤。这些目标将通过使用 用结核分枝杆菌/艾滋病毒混合感染的人源化小鼠进行体内研究，并用分离的肺M进行体外机制研究。 我们工作的预期结果是，我们对艾滋病毒如何操纵 宿主对结核分枝杆菌的炎症反应促进侵袭性疾病。这些结果的积极影响将是 临床干预恢复正常宿主免疫和减少疾病的新靶点的确定 数以百万计的艾滋病毒感染者。

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.