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: 9753887
• 负责人: Michael Stephen Glickman
• 金额: $ 675.69万
• 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/9753887
• 关键词: Adopted; CD4 Positive T Lymphocytes; Defect; Drug Tolerance; Drug-sensitive; Failure; Genetic; HIV Seronegativity; Haiti; Human; Hypersensitivity skin testing; Immune system; Immunity; Immunologics; Individual; Infection; Instruction; Interferon Type II; Knowledge; Memorial Sloan-Kettering Cancer Center; Microbiology; Minority; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Relapse; Research; Research Personnel; TNF gene; Tuberculosis; Universities; adaptive immune response; antimicrobial; insight; latent infection; medical schools; pathogen; prospective; therapy duration; tuberculosis treatment

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。谁估计这一点 世界大约三分之一的人口具有阳性的皮肤测试，反映了长期适应性免疫 对MTB抗原的反应。这些人被认为具有实际或潜在的潜在MTB感染 （LTBL）。其中，无法前瞻性识别的少数族裔会发展出肺结核 （TB）具有正常免疫力的二氨酸。活跃的结核病对那些 以前出乎意料，患有LTBL的人通常是致命的，如果没有治疗。足够数量的CD4 T 细胞，肿瘤坏死因子α（TNFα）和干扰素 - γ（IFNY）的对照确定剂 主要结核病，但绝大多数艾滋病毒阴性患者均未定义缺陷 在这些途径中。 MTB在人类宿主中保持潜在的能力以及相关的失败 对潜在感染个体的刻板印象MTB的人类免疫系统知之甚少。抗菌 对药物敏感的MTB进行主动感染的治疗是有效的，但是当前的药物必须持续6个月 实现无继电器固化速率> 95％。长时间治疗的必要条件是可以归因于 具有普遍对药物敏感的MTB采用表型耐药的持续状态的能力 当前药物不容易对其进行灭菌。尽管付出了巨大的努力来理解这两个关键 MTB感染的特征 - 律和持久性 - 关于遗传的问题仍然存在 两者的免疫学和微生物贡献者。我们试图通过 结核病研究部门（TBRU），该研究人员在Weill Cornell医学院（WCMC）的调查员， 洛克菲勒大学（RU）和纪念Sloan Kettering癌症中心（MSKCC），带有选定的外部 合作者，并借鉴海地与WMC附属的Gheskio中心的患者，以洞悉 人类感染期间MTB的潜伏期和持久性。