Determinants of Paucibacillary Mtb Infection in Mice

小鼠少杆菌 Mtb 感染的决定因素

基本信息

批准号：
10430228
负责人：
SABINE EHRT
金额：
$ 57.25万
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/10430228
关键词：
Affect Aftercare Agar Alveolar Macrophages B-Lymphocytes Biological Markers Biological Response Modifiers Biotin Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Chronic Clinical Colony-forming units Dexamethasone Disease Environment Essential Genes First Independent Research Support and Transition Awards Genes Human Immune Immunity Immunophenotyping Immunosuppression Infection Integration Host Factors Leukocytes Ligase Measures Messenger RNA Modeling Mouse Strains Mus Mycobacterium tuberculosis Natural Killer Cells Patients Persons Pharmacology Physiological Population Predisposition Proteins Recurrent disease Regulon Relapse SCID Mice Symptoms T-Lymphocyte Testing Time Tuberculosis chemotherapy chronic infection disorder risk high risk immunopathology in vivo insight interstitial macrophage mouse model mutant prevent relapse prediction relapse risk thioredoxin reductase transcriptome transcriptomics tuberculosis chemotherapy

项目摘要

Tuberculosis (TB) chemotherapy eliminates disease symptoms, but often fails to sterilize Mycobacterium tuberculosis (Mtb) leaving apparently cured TB patients at risk of disease relapse. How Mtb survives during post- treatment persistent infections (PTPI) is ill defined and we lack a full understanding of the immune determinants that prevent progression to active TB (relapse). We developed a paucibacillary (low bacterial numbers) mouse model that mimics PTPI in in humans. We found that silencing of in vivo essential genes cured Mtb infections in mice to the extent that colony forming units (CFU) were no longer detected on agar plates. However, as in humans, mice were often not sterilized, and paucibacillary infection resulted in relapse TB. Our model allows us to interrogate both, the mechanisms that enable Mtb to persist despite host immunity and the host factors that are required to control and sterilize Mtb infection. We will use this model to (1) compare post-treatment persistent infection (PTPI) in mice and humans (2) determine the importance of specific leukocyte subsets for the establishment or control of paucibacillary Mtb infection and (3) identify Mtb genes that are required for paucibacillary persistence.

结核病 (TB) 化疗可以消除疾病症状，但通常无法杀灭分枝杆菌结核病 (Mtb) 使表面已治愈的结核病患者面临疾病复发的风险。 Mtb 如何在后疫情时代生存治疗持续性感染（PTPI）的定义不明确，我们对免疫决定因素缺乏充分的了解防止进展为活动性结核病（复发）。我们开发了一种模拟人类 PTPI 的少杆菌（低细菌数量）小鼠模型。我们发现体内必需基因的沉默可以治愈小鼠的结核分枝杆菌感染，其程度达到菌落形成单位（CFU）在琼脂平板上不再检测到。然而，与人类一样，小鼠通常没有被绝育，并且少杆菌感染导致结核病复发。我们的模型允许我们询问这两种机制尽管存在宿主免疫以及控制和消灭 Mtb 所需的宿主因素，Mtb 仍然能够持续存在感染。我们将使用该模型来 (1) 比较小鼠和人类的治疗后持续感染 (PTPI) (2) 确定特定白细胞亚群对于建立或控制少杆菌 Mtb 的重要性 (3) 识别少杆菌持续所需的 Mtb 基因。