Determinants of Paucibacillary Mtb Infection in Mice

小鼠少杆菌 Mtb 感染的决定因素

• 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
• 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

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）化学疗法消除了疾病症状，但通常未能对分枝杆菌进行消毒 结核病（MTB）使明显治愈的结核病患者有疾病复发的风险。 MTB如何在后期生存 治疗持续感染（PTPI）的定义不明，我们缺乏对免疫决定因素的完全理解 这可以防止进展为主动结核（复发）。 我们开发了一种模仿人类PTPI的小鼠模型（细菌数低）。我们发现 体内必需基因的沉默使小鼠中的MTB感染治愈了菌落形成单位（CFU）的程度 不再在琼脂板上检测到。但是，就像在人类中一样，小鼠通常不会被灭菌，并且 paucibibacillary感染导致复发结核病。我们的模型使我们能够审问这两个机制 尽管宿主免疫力和控制和消毒所需的宿主因素，使MTB能够持续存在 感染。我们将使用此模型来（1）​​比较小鼠和人类中治疗后持续感染（PTPI） （2）确定特定白细胞子集对paucibaCillary MTB的建立或控制的重要性 感染和（3）识别paucibainlary持久性所需的MTB基因。