Determinants of Paucibacillary Mtb Infection in Mice

小鼠少杆菌 Mtb 感染的决定因素

• 批准号: 10268807
• 负责人: SABINE EHRT
• 金额: $ 45.99万
• 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/10268807
• 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; 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

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）化疗消除了疾病症状，但往往无法杀灭分枝杆菌 结核病（Mtb）使明显治愈的结核病患者面临疾病复发的风险。结核杆菌如何在感染后存活 治疗持续性感染（PTPI）是不明确的，我们缺乏对免疫决定因素的全面了解 预防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治愈了小鼠中的结核分枝杆菌感染， 在琼脂平板上不再检测到。然而，与人类一样，小鼠通常没有绝育， 少杆菌感染导致结核病复发。我们的模型允许我们询问两者， 使结核分枝杆菌能够持续存在，尽管宿主免疫力和宿主因素是控制和消灭结核分枝杆菌所必需的 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建立或控制少杆菌型Mtb的重要性 感染和（3）鉴定少杆菌持久性所需的Mtb基因。