权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9129330
负责人：
Janice J Endsley
金额：
$ 63.76万
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：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9129330
关键词：
Address Age Aggressive course Alveolar Macrophages Amines Animal Model Anti-Bacterial Agents Anti-Retroviral Agents Antibacterial Response Antitubercular Agents Arginine Biological Assay Biological Availability CD4 Positive T Lymphocytes Caspase-1 Cause of Death Cells Clinical Complement Controlled Study Data Defect Development Diet Disease Drug Interactions Environment Functional disorder Granulomatous Growth HIV HIV-1 HIV-2 Health Immune Immune System Diseases Immune response Immunity In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Interferons Interleukin-1 Interleukin-17 Intervention Knowledge Life Lung Malabsorption Syndromes Measures Mediating Metabolism Modeling Molecular Mus Mycobacterium tuberculosis Necrosis Neutrophil Infiltration Nitric Oxide Outcome Pathology Pathway interactions Persons Play Population Production Public Health Pulmonary Pathology Regimen Reporter Research Risk Role Serum Signal Transduction Site Splenocyte Structure of parenchyma of lung T-Cell Depletion T-Lymphocyte TNF gene Testing Tissues Tuberculosis Viral Virus Diseases Virus Replication Work abstracting animal imaging arginase bactericide base chemokine chemotherapy co-infection cytokine gain of function human disease human subject improved in vivo inhibitor/antagonist insight microbial mouse model mycobacterial neutrophil nitrosative stress novel pathogen research study response restoration targeted treatment

项目摘要

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.