Determinants of Paucibacillary Mtb Infection in Mice

小鼠少杆菌 Mtb 感染的决定因素

• 批准号: 10621309
• 负责人: SABINE EHRT
• 金额: $ 45.82万
• 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/10621309
• 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; Macrophage; Measures; Messenger RNA; Modeling; Mouse Strains; Mus; Mycobacterium tuberculosis; Natural Killer Cells; Patients; Persons; Pharmacology; Physiological; Population; Predisposition; Proteins; Recommendation; Recurrent disease; Regulon; Relapse; SCID Mice; Symptoms; T-Cell Depletion; T-Lymphocyte; Testing; Time; Tuberculosis; chemotherapy; chronic infection; disorder risk; high risk; immunopathology; in vivo; insight; interstitial; 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（TB）化疗消除了疾病症状，但往往不能对分枝杆菌进行灭菌