Tri-Institutional TB Research Unit: Persistence and Latency

三机构结核病研究单位：持续性和潜伏期

• 批准号: 9081457
• 负责人: Michael Stephen Glickman
• 金额: $ 721.51万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9081457
• 关键词: Adopted; CD4 Positive T Lymphocytes; Defect; Drug-sensitive; Failure; Genetic; HIV; Haiti; Human; Hypersensitivity skin testing; Immune system; Immunity; Immunologics; Individual; Infection; Instruction; Interferon Type II; Knowledge; Memorial Sloan-Kettering Cancer Center; Minority; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Relapse; Research; Research Personnel; TNF gene; Tuberculosis; Universities; adaptive immunity; antimicrobial; insight; medical schools; pathogen; therapy duration

Mycobacterium tuberculosis (Mtb) is one of the world's most successful pathogens. WHO estimates that about one third of the world's population has a positive skin test that reflects a long-term adaptive immune response to Mtb antigens. These individuals are considered to have actual or potential latent Mtb infection (LTBl). Among them, a minority that cannot be identified prospectively will develop reactivation tuberculosis (TB) despite having apparently normal immunity. Active TB can be contagious both to those who were previously unexposed and those with LTBl and is usually lethal if untreated. Adequate numbers of CD4 T cells, tumor necrosis factor alpha (TNFα), and interferon-gamma (IFNy) are validated determinants of control of primary TB, but the vast majority of HIV negative patients with reactivation TB do not have defined defects in these pathways. The ability of Mtb to remain latent within the human host, and the related failure of the human immune system to sterilize Mtb in latently infected individuals, are poorly understood. Antimicrobial therapy for active infection by drug-sensitive Mtb is effective, but current drugs must be given for 6 months to achieve relapse-free cure rates of >95%. The necessity for this prolonged duration of therapy is attributable to the ability of genetically drug-sensitive Mtb to adopt a phenotypically drug-tolerant, persistent state in which it is not readily sterilized by current drugs. Despite substantial efforts to understand these two critical features of Mtb infection—latency and persistence—fundamental questions remain about the genetic, immunologic, and microbiologic contributors to both. We seek to close this knowledge gap through a Tuberculosis Research Unit (TBRU) that unites investigators at Weill Cornell Medical College (WCMC), Rockefeller University (RU), and Memorial Sloan Kettering Cancer Center (MSKCC), with selected external collaborators, and draws on patients at the WMC-affiliated GHESKIO Centres in Haiti to provide insight into latency and persistence of Mtb during human infection.

世界卫生组织估计，结核分枝杆菌 (Mtb) 是世界上最成功的病原体之一。 世界上约三分之一的人口皮肤测试呈阳性，反映了长期的适应性免疫系统 对 Mtb 抗原的反应 这些个体被认为具有实际或潜在的潜在 Mtb 感染。 (LTB1)。 (结核病) 尽管具有明显正常的免疫力，但活动性结核病可能会传染给那些患有结核病的人。 以前未接触过的患者以及患有LTB1的患者，如果未经治疗，通常是致命的。 细胞、肿瘤坏死因子 α (TNFα) 和干扰素 γ (IFNy) 是经过验证的控制决定因素 的原发性结核病，但绝大多数艾滋病毒阴性的结核病再激活患者没有明确的缺陷 Mtb 在人类宿主体内保持潜伏的能力，以及相关的失败。 人类免疫系统对潜伏感染者的结核分枝杆菌的杀灭作用，人们知之甚少。 对药物敏感的 Mtb 活动性感染的治疗是有效的，但目前的药物必须给予 6 个月才能 实现>95%的无复发治愈率是因为需要延长治疗时间。 遗传药物敏感性结核分枝杆菌在表型上采取耐药、持久状态的能力 尽管我们付出了大量努力来了解这两种关键因素，但目前的药物仍无法轻易消除这种情况。 结核分枝杆菌感染的特征——潜伏期和持续性——关于遗传、 我们寻求通过免疫学和微生物学方面的知识来缩小这一知识差距。 结核病研究中心 (TBRU) 联合了威尔康奈尔医学院 (WCMC) 的研究人员， 洛克菲勒大学 (RU) 和纪念斯隆凯特琳癌症中心 (MSKCC)，以及选定的外部 合作者，并利用海地 WMC 附属 GHESKIO 中心的患者提供见解 人类感染期间 Mtb 的潜伏期和持续时间。