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

 描述(由申请人提供)： 结核病(TB)是艾滋病毒感染者死亡的主要原因。在CD4+T细胞耗尽之前，结核病的风险增加，并可能在通过抗逆转录病毒(ARV)治疗恢复T细胞后继续存在。由于两种疾病的侵袭性病程，混合感染者的治疗具有挑战性；这是一个临床问题，当联合使用抗逆转录病毒药物和结核病化疗时，药物相互作用和吸收不良问题进一步复杂化。应对这些临床挑战需要对合并感染的病理生理学有更多的了解。由于支持艾滋病毒复制的动物模型的可获得性有限，该领域出现了严重的知识缺口。为了解决这一差距，我们在BLT人源化小鼠(HuMouse)中开发了一种新的结核病/艾滋病毒模型，该模型复制了人类疾病的重要病理和免疫学特征。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，我们已经确定了肺部M-φ合并感染协同作用的候选分子机制，该机制促进了促炎环境和促进分枝杆菌增殖。此R01应用的目的是使用新的结核/艾滋病毒混合感染的胡小鼠模型来进一步阐明艾滋病毒感染扰乱肺Mφ对结核分枝杆菌的天然免疫反应的机制。我们的假设是，由于HIV-1感染导致的肺Mφ偏振导致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，减少细菌清除，增加组织坏死。我们有三个单独的假设：1)宿主Mφ对细胞内结核分枝杆菌感染的清除减少，因为竞争一氧化氮合成和艾滋病毒复制所需的L-精氨酸；2)艾滋病毒和结核分枝杆菌混合感染通过炎症依赖激活宿主Mβ中的IL-1φ来驱动促炎肺环境；以及3)由于共感染的促炎环境导致Th17细胞偏向导致依赖于IL-17的中性粒细胞在肺内的募集和损伤。这些目标将通过使用结核分枝杆菌/艾滋病毒共同感染的人源化小鼠的体内研究和分离的肺Mφ的体外机制研究来实现。我们工作的预期结果是，我们在理解艾滋病毒如何操纵宿主对结核分枝杆菌的炎症反应以促进侵袭性疾病方面取得了重大进展。这些结果的积极影响将是确定新的目标，在临床上进行干预，以恢复正常的宿主免疫，并改善数百万艾滋病毒感染者的细菌清除。

 DESCRIPTION (provided by applicant): 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 Mφ 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 Mφ to Mtb. Our hypothesis is that skewed polarization of pulmonary Mφ due to HIV-1 infection drives a hyperinflammatory response to Mtb, which in turn produces neutrophil-mediated lung damage, reduced bacterial clearance, and increased tissue necrosis. We have three aims to test the following individual hypotheses that 1) host Mφ clearance of intracellular Mtb infection is decreased because of competition for L-arginine needed for both nitric oxide synthesis and HIV replication, 2) HIV and Mtb co-infection drive a pro-inflammatory lung environment via inflammasome-dependent activation of IL-1β in host Mφ, and 3) 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 Mφ. 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 the identification of new targets to intervene clinically to restore normal host immunity and improve bacterial clearance in millions of HIV-infected people.