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（Mycobacterium tuberculosis，Mtb）是世界上最成功的病原体之一。卫生组织估计 世界上大约三分之一的人口的皮肤测试呈阳性，反映了长期的适应性免疫 对Mtb抗原的反应。这些人被认为有实际或潜在的潜伏性结核分枝杆菌感染 （LTBI）。其中，不能前瞻性识别的少数人会发展为再活化结核 (TB)尽管他们的免疫力很正常活动性结核病可以传染给那些 先前未暴露的和具有LTB 1的那些，并且如果不治疗通常是致命的。足够数量的CD 4 T 细胞、肿瘤坏死因子α（TNFα）和干扰素γ（IFN γ）是经验证的控制决定因素 但绝大多数HIV阴性的复发性结核病患者没有明确的缺陷 在这些途径中。Mtb在人类宿主中保持潜伏的能力，以及与Mtb相关的免疫失败， 人类免疫系统消灭潜伏感染个体中Mtb的能力知之甚少。抗菌 对药物敏感的结核分枝杆菌活动性感染的治疗是有效的，但目前的药物必须给予6个月， 达到> 95%的无复发治愈率。延长治疗时间的必要性可归因于 基因药物敏感的结核分枝杆菌采取表型耐药，持久状态的能力， 其不容易被当前的药物消毒。尽管我们做了大量的努力来理解这两个关键问题， Mtb感染的特征-潜伏期和持续性-基本问题仍然是关于遗传， 免疫学和微生物学的贡献者。我们寻求通过一个 结核病研究单位（TBRU）联合威尔康奈尔医学院（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），与选定的外部 合作者，并借鉴患者在WMC附属GHESKIO中心在海地提供深入了解 人类感染结核分枝杆菌潜伏期和持续期。