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。世卫组织估计