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。