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.

结核分枝杆菌(Mtb)是世界上最成功的病原体之一。世卫组织估计 世界上约三分之一的人口皮肤测试呈阳性，这反映了长期的适应性免疫 对结核分枝杆菌抗原的反应。这些人被认为有实际或潜在的结核分枝杆菌感染。 (LTB1)。在这些人中，少数人不能被预期识别，将会发展为复活型结核病。 (结核病)，尽管有明显的正常免疫力。活动性结核病可能会传染给那些 以前未接触过的和患有LTBl的人，如果不治疗，通常是致命的。足够数量的CD4T 细胞、肿瘤坏死因子α和干扰素-γ是被证实的控制决定因素 但绝大多数HIV阴性的复活型结核病患者没有明确的缺陷 在这些小路上。结核分枝杆菌在人类宿主内保持潜伏的能力，以及与之相关的 人类免疫系统对潜伏感染的结核分枝杆菌的灭菌作用还知之甚少。抗菌剂 对药物敏感的结核分枝杆菌活动性感染的治疗是有效的，但目前的药物必须服用6个月至 达到95%的无复发治愈率。这种延长疗程的必要性是可以归因于 与遗传药物敏感的结核分枝杆菌采用表型耐药、持续状态的能力有关 它不容易被现有的药物消毒。尽管做出了大量努力来理解这两个关键的 结核分枝杆菌感染的特征-潜伏期和持久性-基本问题仍然存在， 免疫学和微生物学对两者都有贡献。我们寻求通过一项 联合威尔·康奈尔医学院(WCMC)研究人员的结核病研究单位(TBRU)， 洛克菲勒大学(RU)和纪念斯隆·凯特琳癌症中心(MSKCC)，选择外部 合作者，并利用海地WMC附属GHESKIO中心的患者提供对 人感染期间结核分枝杆菌的潜伏期和持久性。