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Autophagy Against Tuberculosis and HIV

自噬对抗结核病和艾滋病毒

基本信息

批准号：
8707081
负责人：
VOJO P DERETIC
金额：
$ 65.6万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707081
关键词：
Acquired Immunodeficiency Syndrome Affect Alleles Antigen-Antibody Complex Area Autophagocytosis Cells Cessation of life Clinical Cytosol Disease Elements Equilibrium Funding HIV Health Human Immune Immunity Incidence Individual Infection Infectious Agent Inflammatory Integration Host Factors Interferon Type I Knowledge Learning Lipids Maintenance Metabolism Microbe Molecular Multi-Drug Resistance Mycobacterium tuberculosis Natural Immunity Non-Insulin-Dependent Diabetes Mellitus Nutritional status Obesity Pathogenesis Pattern Pharmaceutical Preparations Physiological Play Population Process Prophylactic treatment Public Health Publishing Regimen Risk Risk Factors Role Solutions Testing Tuberculosis Viral Proteins Virus Work World Health Organization base cytokine drug development killings latent infection macrophage novel strategies nutrition outcome forecast pandemic disease pathogen prevent prophylactic response therapy development tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): Tuberculosis (TB) and acquired immunodeficiency syndrome (AIDS) are diseases of exceptional public health significance. Their importance is further heightened by the global TB-AIDS co-pandemic. A co-infection with the respective etiologic agents, Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) alters the course of diseases caused by each infectious agent alone. Typically, only 10% of Mtb infections progress to clinically active TB in the absence of HIV. Instead, a controlled, long lasting asymptomatic infection, referred to as latent TB infection (LTBI), is established. Establishment of LTBI and the drivers of progression to active disease are not fully understood. Previously untried approaches are needed to move the field forward. In this application, we will take a new approach by demonstrating the key role of autophagy in maintaining the balance between LTBI and progression to active TB, and as a process targeted by the virus during HIV-Mtb co-infection. Autophagy is a newly recognized but nevertheless evolutionary ancient innate immunity mechanism that acts as a cell-autonomous defense against a variety of intracellular pathogens including Mtb. Our published work and studies by others indicate that autophagy, when appropriately induced, is a significant anti-Mtb cell- autonomous innate immunity defense. We propose that autophagy prevents progression to active disease and favors LTBI. The host-protective action is based on two effector functions of autophagy: first, it eliminates intracellulr Mtb, and, second, it suppresses pathogenic cytokine responses. In this project, we will test the hypothesis that autophagy maintains a host-protective state and prevents progression to active TB, whereas intrinsic host factors or HIV co-infection interfere with autophagy and promote clinically overt TB. If this hypothesis is correct, pharmacological targeting of autophagy and specific processes identified in this project will provide new prophylactic and treatment opportunities. The specific aims of this application are: Specific Aim 1. Determine whether and how HIV interferes with autophagic elimination of Mtb in co- infected macrophages. Mechanistically, we will define the role of the HIV protein Nef and its alleles from clinical HIV isolates and test their capacity to inhibit Beclin 1-dependent autophagy and suppress Mtb elimination in macrophages. Specific Aim 2. Determine whether and how autophagy inhibits type I interferon (IFN) responses associated with progression to active disease. We will test whether autophagy prevents induction of type I IFN associated with active TB, and how this affects TB pathogenesis. Specific Aim 3. Define whether and how cellular neutral lipid loads affect autophagic control of Mtb. To determine how intrinsic host factors (in the absence of HIV) influence autophagy's ability to maintain a host- protective state-i.e. the LTBI status-we will tes whether host cell lipid stores and imbalances in cellular lipid loads affect autophagic control of Mtb.

描述（由申请人提供）：