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。 活动性结核病是由M.结核病（Mtb）导致约150万人死亡 每年。结核病/艾滋病毒合并感染对全球结核病负担有重大贡献。控制结核病的失败 因为缺乏有效的疫苗因此，迫切需要新的疫苗。我们不完全 了解保护相关免疫反应的特性。 我们最近的研究表明，MtbΔsigH，一个缺乏应激反应调节因子SigH的突变体，完全被 在猕猴肺中的存活减弱，并激发深刻和富有成效的肺免疫应答。气溶胶 用这种突变体接种疫苗可以完全保护猕猴免受致命性肺结核的侵害， 和保护远远超过BCG接种所观察到的。Δ sigH疫苗似乎可以保护 通过募集保护性记忆T细胞应答肺来抵抗Mtb的致死性攻击。所以我们 有一个前所未有的机会，更好地了解保护免受结核病感染的相关因素， 研究这些猕猴的反应。此外，我们现在表明，非致病性感染， 具有MtbΔsigH的猕猴肺不像Mtb特异性LTBI那样通过与SIV共感染而重新激活。 然而，大多数感染LTBI的Mtb动物在与SIV共感染时重新激活感染。因此 在SIV（因此可能是HIV）合并感染的情况下似乎是安全的。 作为本申请的一部分，我们寻求鉴定免疫相关的保护相关T细胞特异性相关物， 与BCG接种或未接种动物相比，在接种前后， 结核病的挑战。此外，我们还将研究这些保护相关反应是否保留在 SIV合并感染的情况。我们将进一步关注B细胞特异性反应， 已发表的数据表明，含有这些细胞的细胞团聚集在受保护动物的肉芽肿中。 !