Determinants of TB control, relapse and reinfection

结核病控制、复发和再感染的决定因素

• 批准号: 10621299
• 负责人: SABINE EHRT
• 金额: $ 256.5万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621299
• 关键词: Aftercare; Antibiotic Therapy; Antibiotics; Antimycobacterial Agents; Antitubercular Antibiotics; Bacillus; Bacteria; Biological; Biological Markers; Blood specimen; Body Fluids; Cells; Chemotherapy-Oncologic Procedure; Clinical; Clinical Data; Country; Disease; Drug Kinetics; Enrollment; Failure; Family; Genes; Genetic; Goals; Growth; Haiti; Human; Human Genetics; Immune; Immune system; Immunologics; Immunophenotyping; Individual Differences; Infection; Infection Control; Integration Host Factors; Knowledge; Length; Machine Learning; Maintenance; Measures; Mediating; Modeling; Mouse Strains; Mus; Mycobacterium tuberculosis; Organ; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Plasma; Population; Predisposition; Process; Recurrence; Relapse; Research Personnel; Resolution; Resources; Role; Sampling; Sampling Studies; Siblings; Sterilization; TYK2; Testing; Tissues; Treatment outcome; Tuberculosis; Work; chemotherapeutic agent; chemotherapy; chronic infection; clinical research site; cohort; data management; design; empowerment; experience; genetic variant; global health; gut microbiome; high dimensionality; high risk; immunopathology; insight; microbiome; microbiome composition; microbiome research; mouse model; next generation sequencing; pathogen; pressure; recruit; relapse prevention; relapse risk; response; success; synergism; transcriptomics; treatment response; tuberculosis chemotherapy; tuberculosis drugs; tuberculosis treatment

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to be a severe global health problem. TB is multifaceted, but a central clinical and microbiologic feature of the disease is the ability of Mtb to resist complete elimination, both by the host immune system and by chemotherapeutic agents with potent growth inhibitory activity. This persistence in the face of immunologic and antibiotic pressure underlies several important facets of TB disease, including 1) the existence of latent tuberculosis infection (LTBI) and, in the setting of immunologic failure of LTBI control, its role in the genesis of active TB and 2) the prolonged course of TB antibiotic therapy, which requires 6 months of multidrug therapy to achieve reliable clinical cure. Rather than producing complete bacterial eradication in all treated subjects, cure following TB chemotherapy is now understood to be an antibiotic induced paucibacillary state in which prevention of relapse depends in part on poorly understood host factors. The host and bacterial determinants that mediate these two interrelated types of persistence are only partially understood, a knowledge gap the Tri-I-TBRU aims to fill. We propose a set of 3 intersecting projects and 3 cores all focused on different facets of the problem of paucibacillary TB, both post treatment and LTBI. The projects will use samples and clinical data from TB cohorts at our clinical site at GHESKIO in Port Au Prince Haiti, to examine the immunologic, microbiomic, transcriptomic, pharmacokinetic, and genetic factors that influence or predict the transition points between paucibacillary states of TB disease and active transmissible infection. These human studies will be compared and contrasted with a new mouse model of paucibacillary infection that will allow us to test mechanistic hypotheses about the host and bacterial determinants of paucibacillary disease. This work with be conducted by a team of highly collaborative investigators who have who have worked well together for several years.

结核分枝杆菌（Mycobacterium tuberculosis，Mtb），结核病（TB）的病原体，仍然是严重的全球性结核病。 健康问题。结核病是多方面的，但该疾病的中心临床和微生物学特征是能够 结核分枝杆菌抵抗完全消除，无论是由宿主免疫系统和化疗剂与有效的 生长抑制活性面对免疫和抗生素的压力，这种坚持是几个 结核病的重要方面，包括1）潜伏性结核感染（LTBI）的存在， LTBI控制的免疫失败，其在活动性TB的发生中的作用和2）TB的病程延长 抗生素治疗，需要6个月的多药治疗才能实现可靠的临床治愈。而不是 在所有接受治疗的受试者中产生完全的细菌根除， 被理解为抗生素诱导的少菌状态，其中复发的预防部分依赖于 对宿主因素知之甚少。介导这两种相互关联的类型的宿主和细菌决定簇 持久性只是部分理解，这是Tri-I-TBRU旨在填补的知识空白。我们建议一套3 交叉项目和3个核心项目都侧重于少杆菌结核病问题的不同方面， 治疗和LTBI。这些项目将使用来自我们临床研究中心的结核病队列的样本和临床数据， 海地Au Prince港的GHESKIO，检查免疫学，微生物组学，转录组学，药代动力学， 以及影响或预测结核病的少菌状态之间的转变点的遗传因素， 活动性传染病这些人类研究将与一种新的小鼠模型进行比较和对比 这将使我们能够测试关于宿主和细菌的机制假设， 少杆菌病的决定因素。这项工作将由一个高度协作的团队进行 几年来一直合作得很好的调查人员。

项目成果

Inborn errors of human transcription factors governing IFN-γ antimycobacterial immunity.

控制 IFN-γ 抗分枝杆菌免疫的人类转录因子的先天性错误。

• DOI: 10.1016/j.coi.2023.102296
• 发表时间: 2023
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: Ogishi,Masato;Yang,Rui;Rosain,Jérémie;Bustamante,Jacinta;Casanova,Jean-Laurent;Boisson-Dupuis,Stéphanie
• 通讯作者: Boisson-Dupuis,Stéphanie

Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites.

• DOI: 10.1073/pnas.2314225120
• 发表时间: 2023-11-14
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Zhang, Peng;Chaldebas, Matthieu;Ogishi, Masato;Al Qureshah, Fahd;Ponsin, Khoren;Feng, Yi;Rinchai, Darawan;Milisavljevic, Baptiste;Han, Ji Eun;Moncada-Velez, Marcela;Keles, Sevgi;Schroeder, Bernd;Stenson, Peter D.;Cooper, David N.;Cobat, Aurelie;Boisson, Bertrand;Zhang, Qian;Boisson-Dupuis, Stephanie;Abel, Laurent;Casanova, Jean- Laurent
• 通讯作者: Casanova, Jean- Laurent

Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis.

• DOI: 10.1084/jem.20220484
• 发表时间: 2023-01-02
• 期刊: The Journal of experimental medicine

Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli.

尽管存在艾滋病毒，但结核分枝杆菌仍具有抵抗力，其肺泡中的 T 细胞和巨噬细胞被激活。

• DOI: 10.21203/rs.3.rs-3889020/v1
• 发表时间: 2024
• 期刊: Research square
• 作者: Schurr,Erwin;Dallmann-Sauer,Monica;Fava,Vinicius;Malherbe,Stephanus;McDonald,Candice;Orlova,Marianna;Kroon,Elouise;Cobat,Aurélie;Boisson-Dupuis,Stéphanie;Hoal,Eileen;Abel,Laurent;Möller,Marlo;Casanova,Jean-Laurent;Walzl,Gerhard