Determinants of TB control, relapse and reinfection

结核病控制、复发和再感染的决定因素

基本信息

批准号：
10268801
负责人：
SABINE EHRT
金额：
$ 275.55万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
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/10268801
关键词：
Address Aftercare Antibiotic Therapy Antibiotics Antimycobacterial Agents Bacillus Bacteria Biological Markers Blood specimen Body Fluids Cells Chemotherapy-Oncologic Procedure Clinical Clinical Data Clinical Microbiology Country Disease Drug Kinetics Enrollment Failure Family Genes Genetic Goals Growth Haiti Human Human Genetics Immune Immune system Immunologics Immunophenotyping Infection Infection Control Integration Host Factors Knowledge Length Machine Learning Maintenance Measures Mediating Modeling Mouse Strains Mus Mycobacterium tuberculosis Organ Patients Pharmaceutical Preparations Pharmacology Plasma Population Predisposition Process Recurrence Relapse Research Personnel Resolution Resources Role Sampling Sampling Studies Ships Siblings Sterilization TYK2 Testing Tissues Treatment outcome Tuberculosis Work chemotherapeutic agent chemotherapy chronic infection clinical research site cohort data management design disorder later incidence prevention 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 risk response success synergism transcriptomics treatment response tuberculosis chemotherapy tuberculosis drugs tuberculosis treatment

项目摘要

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），结核病的病因（TB）继续是严重的全球健康问题。 TB是多方面的，但是该疾病的中心临床和微生物学特征是 MTB可以通过宿主免疫系统和具有有效的化学治疗剂来抵抗完全消除生长抑制活性。面对免疫和抗生素压力的这种持久性是几个结核病疾病的重要方面，包括1）存在潜在结核病感染（LTBI），并在情况下 LTBI控制的免疫失败，其在活性TB的起源中的作用和2）TB的延长过程抗生素疗法需要6个月的多药治疗才能获得可靠的临床治疗。而不是在所有治疗的受试者中产生完全消除细菌，现在治愈结核病化疗后是理解是一种抗生素诱导的paucibainary态，其中预防复发部分取决于理解的宿主因素不足。介导这两种相互关联的类型的宿主和细菌决定因素持久性仅是部分理解的，这是一个知识差距Tri-i-TBRU旨在填补。我们提出了一组3 相交的项目和3个核心都集中在paucibaCillary结核病问题的不同方面治疗和LTBI。这些项目将在我们的临床现场使用TB队列的样品和临床数据海地港口的Gheskio，用于检查免疫学，微生物，转录组，药代动力学，以及影响或预测结核病疾病的paucibaCillary态和的遗传因素主动传播感染。这些人类研究将被比较并与新的小鼠模型进行比较 paucibainapary感染，这将使我们能够检验有关宿主和细菌的机械假设贫血疾病的决定因素。这项工作由一支高度协作的团队进行共同工作好几年的调查员。