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: 9204905
• 负责人: Smriti Mehra
• 金额: $ 16.65万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204905
• 关键词: Adult; Aerosols; Animals; Antibody Formation; Antigens; Attenuated; B-Cell Activation; B-Lymphocytes; Biological Assay; Breathing; Cell Wall; Cells; Cessation of life; DNA Damage; DNA Vaccines; Data; Development; Disease; Dissection; Dose; Epitopes; Exhibits; Experimental Models; Failure; Figs - dietary; Genes; Genus Mycobacterium; Grant; Granuloma; Granulomatous; HIV; Human; Hypoxia; Immune; Immune response; Immune system; Immunity; Individual; Infection; Infection Control; Lead; Lesion; Life; 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; Staging; Stress; Subunit Vaccines; T cell response; T-Cell Receptor; T-Lymphocyte; Time; Tissues; Tuberculosis; Tuberculosis Vaccines; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Virulence Factors; Work; abstracting; adaptive immunity; aerosolized; antigen challenge; base; biological adaptation to stress; co-infection; cytokine; deep sequencing; mouse model; mutant; novel; novel vaccines; pandemic disease; pulmonary vaccination; research study; response; stem; transcriptome sequencing; 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 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。 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 了解与保护相关的免疫复杂的身份。 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。 作为本应用的一部分，我们试图确定与保护相关的T细胞特异性免疫相关性 在与BCG接种或未接种疫苗的动物相对于BCG接种疫苗的猕猴，无论是在之前还是之后 MTB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共同感染的设置。根据初步和 公开的数据，这些数据簇含有这些细胞，积聚在受保护动物的肉芽肿中。 呢