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Correlates of protection from TB and TB/AIDS comorbidity

预防结核病和结核病/艾滋病合并症的相关性

基本信息

批准号：
9203508
负责人：
Smriti Mehra
金额：
$ 23.72万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
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：
2016-06-22 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9203508
关键词：
Acquired Immunodeficiency Syndrome Adult Aerosols Animals Antigen Presentation Antigens Attenuated Biological Assay Breathing Cell Wall Cells Cessation of life Comorbidity DNA Damage DNA Vaccines Development Disease Dose Epitopes Exhibits Experimental Models Failure Figs - dietary Genes Genus Mycobacterium Grant Granulomatous HIV Human Hypoxia Immune Immune response Immune system Immunity Infection Investigation Life Life Cycle Stages Lipids Lung Macaca Memory Modeling Monkeys Mycobacterium tuberculosis Natural Immunity Oxidative Stress Pathology Peripheral Blood Mononuclear Cell Phagocytes Proteins Publishing Pulmonary Tuberculosis Recruitment Activity SIV Sampling Specificity Staging Staining method Stains Stress Subunit Vaccines T cell response T-Lymphocyte Time Tissues Tuberculosis Tuberculosis Vaccines United States National Institutes of Health Vaccinated Vaccination Vaccines Virulence Factors Work abstracting aerosolized antigen challenge base biological adaptation to stress co-infection cytokine immunogenic macrophage mouse model mutant novel vaccines pandemic disease programs pulmonary vaccination research study response stem tuberculosis immunity vaccination against tuberculosis vaccine candidate

项目摘要

Abstract. Active TB disease, resulting from productive infection with M. tuberculosis (Mtb), causes ~1.5 million deaths annually. Mtb/HIV co-infections contribute significantly to the global TB burden. The failure to control TB stems from the lack of an effective vaccine. New vaccines are therefore urgently needed. We do not completely understand both the breadth of antigens recognized by the host immune system and identity of protection- associated immune responses. Our recent work has shown that MtbΔsigH, a mutant lacking the stress-response regulator SigH, is completely attenuated for survival in macaque lungs, and elicits profound and productive lung immune responses. Aerosol vaccination with this mutant completely protects macaques from lethal pulmonary TB and both the responses and protection far exceed that observed for BCG vaccination. It appears that ΔsigH-vaccination protects against lethal challenge with Mtb by a recruiting a protective memory T cell response to the lung. Therefore, we have an unprecedented opportunity to better understand the correlates of protection from Mtb infection by studying responses elicited in these macaques. Furthermore, we now show that the nonpathogenic infection of macaque lungs with MtbΔsigH is not reactivated by co-infection with SIV, as is the case for Mtb-specific LTBI. A majority of Mtb infected animals with LTBI however reactivate infection when co-infected with SIV. Therefore appears to be safe in the setting of SIV (hence possibly HIV) co-infection. As part of this application we seek to identify protection-associated correlates of immunity in macaques vaccinated with ΔsigH, relative to BCG vaccinated or unvaccinated animals, both prior to and after Mtb challenge. Furthermore, we will also study if these protection-associated responses are retained in the setting of SIV co-infection. !

摘要。