Tri-Institutional TB Research Unit: Persistence and Latency

U19申请总体描述（由申请人提供）：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，世界上约有三分之一的人口皮肤试验呈阳性，这反映了对结核分枝杆菌抗原的长期适应性免疫反应。这些人被认为有实际或潜在的潜伏结核杆菌感染（LTBl）。其中，少数不能前瞻性识别的人，尽管具有明显正常的免疫力，但会发展为再活动性结核病（TB）。活动性结核既可传染给以前未接触过的人，也可传染给LTBl患者，如果不治疗通常是致命的。足够数量的CD4 T细胞、肿瘤坏死因子α (TNF)和干扰素γ (IFN)被证实是控制原发性结核的决定因素，但绝大多数HIV阴性的再活化结核患者在这些途径中没有明确的缺陷。人们对结核分枝杆菌在人类宿主中潜伏的能力以及人类免疫系统在潜伏感染个体中对结核分枝杆菌进行灭菌的相关失败知之甚少。对药物敏感型结核分枝杆菌的活动性感染进行抗菌治疗是有效的，但目前的药物治疗必须持续6个月才能达到95%以上的无复发治愈率。这种延长治疗时间的必要性是由于基因药物敏感的结核分枝杆菌能够采取一种表型上的耐药、持续状态，在这种状态下，它不容易被现有药物消毒。尽管在了解结核分枝杆菌感染的这两个关键特征——潜伏期和持久性方面做了大量的努力，但遗传、免疫学和微生物学对这两个特征的影响仍然存在根本性的问题。我们试图通过一个结核病研究单位（TBRU）来缩小这一知识差距，该单位联合了威尔康奈尔医学院（WCMC）、洛克菲勒大学（RU）和纪念斯隆凯特琳癌症中心（MSKCC）的研究人员，以及选定的外部合作者，并吸引了海地wmc附属的GHESKIO中心的患者，以深入了解人类感染期间结核的潜伏期和持久性。

DESCRIPTION OF THE OVERALL U19 APPLICATION (as provided by applicant): 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 (TNF¿), and interferon-gamma (IFN?) 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 substantal 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 Centers in Haiti to provide insight into latency and persistence of Mtb during human infection.