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（Mtb），结核病（TB）的病原体，继续是一个严重的全球

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