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

• 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
• 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

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. !

抽象的。 活性结核病是由结核分枝杆菌（MTB）引起的，导致约150万人死亡 MTB/HIV共同感染对全球结核病负担产生了重大贡献。无法控制结核茎 由于缺乏有效的疫苗。因此，迫切需要新的疫苗。我们不是完全 了解宿主免疫系统认可的抗原的广度和保护的身份 - 相关的免疫复杂。 我们最近的工作表明，缺乏应力反应调节器的突变体MTBΔSigh完全是 减弱在猕猴肺中生存，并引起深刻而富有生产力的肺免疫调查。气雾剂 使用该突变体的疫苗接种完全可以保护猕猴免受致命肺结核的侵害和两种反应 保护远远超过了BCG疫苗接种的保护。看来ΔSigh-vaccination保护 通过招募对肺部的保护性记忆T细胞反应来反对对MTB的致命挑战。因此，我们 有前所未有的机会，可以更好地了解MTB感染的保护相关性 研究这些猕猴引起的响应。此外，我们现在表明 与MTB特异性LTBI一样，与MTBΔSigh的猕猴肺未通过与SIV共感染重新激活。 然而，大多数MTB感染LTBI的动物与SIV共同感染时会重新激活感染。所以 在SIV（因此可能的HIV）共同感染的情况下，似乎是安全的。 作为本应用程序的一部分，我们试图确定猕猴中免疫的相关性 在MTB之前和之后，与BCG接种疫苗或未接种的动物接种ΔSigh 挑战。此外，我们还将研究这些与保护相关的响应是否保留在环境中 SIV共同感染。 呢