Tri-Institutional TB Research Unit: Persistence and Latency

U19整体申请说明(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，世界上约三分之一的人口皮肤测试呈阳性，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结核分枝杆菌潜伏感染(LTB 1)。其中，尽管具有明显的正常免疫力，但无法前瞻性识别的少数人将发展为再激活结核病(TB)。活动性结核病对那些以前没有接触过结核病的人和患有长期结核病的人都可能是传染性的，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。是被证实的控制原发结核病的决定因素，但绝大多数艾滋病毒阴性的复活结核病患者在这些途径中没有明确的缺陷。结核分枝杆菌在人类宿主内潜伏的能力，以及人类免疫系统对潜伏感染的人的结核分枝杆菌灭菌相关的失败，人们了解得很少。对于药物敏感的结核分枝杆菌活动性感染，抗菌治疗是有效的，但目前的药物必须服用6个月才能达到95%的无复发治愈率。之所以需要这样长时间的治疗，是因为对遗传药物敏感的结核分枝杆菌有能力采用一种表型耐药的持久状态，在这种状态下，它不容易被现有药物灭菌。尽管人们努力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-但关于两者的遗传、免疫学和微生物学因素的基本问题仍然存在。我们寻求通过一个结核病研究单位(TBRU)弥合这一知识差距，该单位将威尔·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)的研究人员与选定的外部合作者联合起来，并利用WMC附属的海地GHESKIO中心的患者来提供对人类感染期间结核杆菌的潜伏期和持久性的洞察。

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.