Chemistry Core

化学核心

• 批准号: 10057814
• 负责人: Jeffrey Aube
• 金额: $ 76.63万
• 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/10057814
• 关键词: Adopted; Antimicrobial susceptibility; Biological Assay; Biological Markers; CD4 Positive T Lymphocytes; Chemistry; Clinical Research; Combined Modality Therapy; Defect; Drug Tolerance; Drug resistance; Essential Genes; Face; Failure; Genetic; Genetic Determinism; Genetic Polymorphism; Genotype; HIV Seronegativity; Haiti; Human; Hypersensitivity skin testing; Immune; Immune system; Immunity; Immunocompetent; Immunologic Factors; Immunologics; In Vitro; Individual; Infection; Interferon Type II; Knowledge; Link; Memorial Sloan-Kettering Cancer Center; Microbiology; Minority; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiology; Population; Pyrazinamide; Regimen; Relapse; Research; Research Personnel; Resuscitation; Risk; Sputum; Sterilization; TNF gene; Treatment Failure; Treatment Protocols; Tuberculosis; Universities; Whole Blood; adaptive immune response; antimicrobial; bactericide; clinically relevant; clinically significant; drug-sensitive; gene product; genetic variant; high risk; improved; in vivo; insight; latent infection; medical schools; member; mouse model; novel therapeutics; pathogen; patient stratification; prognostic; prospective; therapy duration; transcriptomics

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 (IFNγ) 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 WCMC-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 世界三分之一的人口具有阳性皮肤测试，反映了长期适应性免疫响应 到MTB抗原。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将发展出重新激活结核病（TB） 尽管显然具有正常的免疫力。主动结核对以前的人都可以传染 未受未经ltbl的未暴露，如果没有治疗，通常是致命的。足够数量的CD4 T细胞，肿瘤 坏死因子α（TNFα）和干扰素 - γ（IFNγ）被验证了原发性控制的决定者 结核病，但绝大多数艾滋病毒阴性患者TB没有定义缺陷 途径。 MTB在人类宿主中保持潜在的能力以及人类的相关失败 对潜在感染个体的刻板印象MTB的免疫系统知之甚少。抗菌治疗 药物敏感的MTB的主动感染是有效的，但必须将目前的药物持续6个月才能实现 无复发的治疗率> 95％。这种延长治疗持续时间的必要归因于 一般对药物敏感的MTB采用表型耐药性，持续状态的能力，在其中 很容易被当前药物灭菌。尽管努力理解MTB的这两个关键特征 感染 - 法律和持久性 - 关于遗传，免疫学和 两者的微生物贡献者。我们试图通过结核病研究部门缩小这一知识差距 （TBRU）将Weill Cornell医学院（WCMC），洛克菲勒大学（RU）和 纪念Sloan Kettering Cancer Center（MSKCC），与选定的外部合作者，并借鉴患者 在海地与WCMC附属的Gheskio中心，可深入了解MTB期间MTB的潜伏期和持久性 人类感染。