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

HIV引起的肺巨噬细胞缺陷加剧结核分枝杆菌合并感染

基本信息

批准号：
9204582
负责人：
Janice J Endsley
金额：
$ 71.94万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9204582
关键词：
Address Aggressive course Alveolar Alveolar Macrophages Animal Model Anti-Bacterial Agents Anti-Retroviral Agents Antibacterial Response Award Biological Assay Biological Availability CASP1 gene CD4 Positive T Lymphocytes Cause of Death Cell Death Cells Clinical Complement Controlled Study Defect Development Disease Drug Interactions Environment Functional disorder Granulomatous Growth HIV HIV-1 Human Immune Immune System Diseases Immune response Immunity In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-17 Intervention Knowledge Life Lung Malabsorption Syndromes Measures Mediating Modeling Molecular Mus Mycobacterium tuberculosis Necrosis Neutrophil Infiltration Outcome Pathology Pathway interactions Persons Play Population Public Health Pulmonary Pathology Research Risk Role Signal Transduction Site Splenocyte T-Cell Depletion T-Lymphocyte TNF gene Testing Tissues Tuberculosis Virus Diseases Virus Replication Work abstracting animal imaging base chemokine chemotherapy co-infection cytokine gain of function human disease human subject humanized mouse immunopathology improved in vivo insight macrophage memory CD4 T lymphocyte microbial monocyte mouse model mycobacterial neutrophil novel novel therapeutics research study response restoration targeted treatment

项目摘要

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.

抽象的结核病 (TB) 是艾滋病毒感染者死亡的主要原因结核病风险增加。先于 CD4+ T 细胞耗竭，并可在抗逆转录病毒 (ARV) 恢复 T 细胞后继续由于两个人的攻击性病程，共同感染者的治疗具有挑战性。疾病；由于药物相互作用和吸收不良问题而变得更加复杂的临床问题结合抗逆转录病毒药物和结核病化疗来应对这些临床挑战需要更大的努力。由于对合并感染病理生理学的理解，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有限。为了解决这一差距，我们开发了一种新型药物。 BLT 人源化小鼠 (HuMouse) 中的 TB/HIV 模型可再现重要的病理和通过使用我们独特的动物模型，我们现在能够研究人类疾病的免疫学特征。 HIV-1 和结核分枝杆菌 (Mtb) 感染在肺部的微生物协同作用结果，我们得到了结果。确定了肺巨噬细胞（M）中共感染协同作用的候选分子机制，可促进 R01 应用的目的是促进炎症环境并增加分枝杆菌增殖。是利用新的HuMouse TB/HIV共感染模型来进一步阐明HIV感染的机制感染破坏了肺部 Mf 对 Mtb 的先天免疫反应。 HIV-1 感染引起的肺 M 中 IL-1 炎症小体依赖性激活驱动对 Mtb 的过度炎症反应，进而产生中性粒细胞介导的肺损伤我们有两个目的来检验以下个别假设：1) HIV 和 Mtb。共感染通过宿主体内炎症小体依赖性 IL-1 激活驱动促炎性肺部环境 M，以及 2) 由于共感染的促炎环境而导致 Th17 细胞偏向的发展，导致 IL-17 依赖性中性粒细胞在肺部的募集和损伤将通过使用来实现。 Mtb/HIV 共感染人源化小鼠的体内研究和离体肺 Mf 的体外机制研究。我们工作的预期成果是我们对艾滋病毒如何操纵病毒的理解取得了重大进展。宿主对 Mtb 的炎症反应会促进侵袭性疾病。确定临床干预的新目标，以恢复正常的宿主免疫力并减少疾病数百万艾滋病毒感染者。