Characterization of Protective Immunity to MTB in a Setting of HIV Coinfection

HIV 合并感染情况下 MTB 保护性免疫的特征

• 批准号: 9302690
• 负责人: Konstantin G Kousoulas
• 金额: $ 13.28万
• 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: 2016-06-24 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302690
• 关键词: Adult; Aerosols; Alpha Cell; Animals; Antibody Formation; Antigens; Attenuated; B-Cell Activation; B-Lymphocytes; Breathing; Cell Wall; Cells; Cessation of life; DNA Damage; DNA Vaccines; Data; Development; Disease; Dissection; Dose; Epitopes; Exhibits; Experimental Models; Failure; Genes; Genus Mycobacterium; Grant; Granuloma; Granulomatous; HIV; Human; Hypoxia; Immune; Immune response; Immune system; Immunity; Immunology procedure; Individual; Infection; Infection Control; Lead; Lesion; Life Cycle Stages; Lung; Macaca; Memory; Methodology; Modeling; Monkeys; Mycobacterium Infections; Mycobacterium tuberculosis; Oxidative Stress; Pathology; Peripheral Blood Mononuclear Cell; Phenotype; Proteins; Publishing; Pulmonary Tuberculosis; Recruitment Activity; SIV; Sampling; Signal Transduction; Specificity; Stress; Subunit Vaccines; T memory cell; T-Cell Receptor; T-Lymphocyte; Time; Tissues; Tuberculosis; Tuberculosis Vaccines; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Virulence Factors; Work; adaptive immune response; aerosolized; antigen challenge; base; biological adaptation to stress; co-infection; cytokine; deep sequencing; experimental study; latent infection; mouse model; mutant; novel; novel vaccines; pandemic disease; pulmonary vaccination; response; stem; transcriptome sequencing; tuberculosis immunity; vaccination against tuberculosis; vaccine candidate; virtual

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 the 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 T cell specific 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. We will further focus on B cell specific responses in the light of preliminary and published data that clusters containing these cells accumulate in granulomas of protected animals. !

抽象的。 由结核分枝杆菌 (Mtb) 有效感染引起的活动性结核病导致约 150 万人死亡 每年。结核分枝杆菌/艾滋病毒混合感染对全球结核病负担造成重大影响。未能控制结核病 由于缺乏有效的疫苗。因此迫切需要新的疫苗。我们不完全 了解与保护相关的免疫反应的特性。 我们最近的工作表明，MtbΔsigH，一种缺乏应激反应调节因子 SigH 的突变体，完全是 其在猕猴肺部的生存能力减弱，并引发深刻而有效的肺部免疫反应。气雾剂 接种这种突变体可以完全保护猕猴免受致命性肺结核的侵害，并且两种反应 和保护作用远远超过卡介苗疫苗接种所观察到的效果。看来 ΔsigH 疫苗接种可以保护 通过招募对肺部的保护性记忆 T 细胞反应来对抗 Mtb 的致命攻击。因此，我们 有一个前所未有的机会更好地了解预防结核分枝杆菌感染的相关性 研究这些猕猴的反应。此外，我们现在表明，非致病性感染 与 Mtb 特异性 LTBI 不同，携带 MtbΔsigH 的猕猴肺不会因与 SIV 共感染而重新激活。 然而，大多数感染 LTBI 的 Mtb 动物在与 SIV 共同感染时会重新激活感染。所以 在 SIV（因此可能是 HIV）合并感染的情况下似乎是安全的。 作为本应用的一部分，我们寻求识别与保护相关的 T 细胞免疫特异性相关性。 相对于接种 BCG 或未接种疫苗的动物，接种 ΔsigH 疫苗之前和之后的猕猴 山地车挑战。此外，我们还将研究这些与保护相关的反应是否保留在 SIV 合并感染的情况。我们将根据初步和研究结果进一步关注 B 细胞特异性反应。 发表的数据表明，含有这些细胞的簇在受保护动物的肉芽肿中积累。 ！