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.

结核病 (TB) 的病原体结核分枝杆菌 (Mtb) 仍然是全球严重的结核病健康问题。结核病是多方面的，但该疾病的一个核心临床和微生物学特征是能够 Mtb 能够抵抗宿主免疫系统和强效化疗药物的完全消除生长抑制活性。这种面对免疫和抗生素压力的持续存在是以下几个原因的基础：结核病的重要方面，包括 1) 潜伏性结核感染 (LTBI) 的存在，以及在这种情况下 LTBI 控制免疫失败的原因、其在活动性结核病发生中的作用以及 2) 结核病病程延长抗生素治疗，需要6个月的多药治疗才能达到可靠的临床治愈。而不是在所有接受治疗的受试者中实现彻底的细菌根除，结核病化疗后的治愈现已成为可能据了解，这是一种抗生素诱导的少杆菌状态，其中复发的预防部分取决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因素持久性仅被部分理解，Tri-I-TBRU 旨在填补这一知识空白。我们建议 3 件套交叉项目和 3 个核心项目均侧重于少杆菌结核问题的不同方面，均是在治疗和 LTBI。这些项目将使用来自我们临床基地的结核病队列的样本和临床数据， GHESKIO 在海地太子港检查免疫学、微生物组、转录组、药代动力学、以及影响或预测结核病和结核病的少杆菌状态之间转变点的遗传因素活动性传染性感染。这些人类研究将与新的小鼠模型进行比较和对比少杆菌感染的研究将使我们能够测试有关宿主和细菌的机制假设少杆菌疾病的决定因素。这项工作由高度协作的团队进行多年来一直合作良好的调查员。