Mesenchynmal stem cells as a protective niche for latent M. tuberculosis

间充质干细胞作为潜伏结核分枝杆菌的保护生态位

• 批准号: 8896188
• 负责人: GILLIAN L BEAMER
• 金额: $ 61.9万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896188
• 关键词: ABCG2 gene; Address; Affect; Anti-Bacterial Agents; Antibiotics; Antigens; Antitubercular Agents; Bacillus (bacterium); Bone Marrow; Cause of Death; Cells; Chronic; Clinical; Confocal Microscopy; Data; Disease; Drug Efflux; Gene Expression; Growth; HIV; HIV Infections; Harvest; Health; Human; Immune; Immunity; Immunologic Deficiency Syndromes; In Vitro; Infection; Infectious Agent; Knowledge; Left; Lesion; Lung; Membrane; Mesenchymal Stem Cells; Microbe; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Newly Diagnosed; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiological Processes; Production; Publishing; Reporter; Resolution; Rifampin; Science; Staging; Stem cells; Stimulus; T cell response; Testing; Therapeutic; Tuberculosis; Tuberculosis Vaccines; Video Microscopy; Virulent; cytokine; drug development; efflux pump; immune activation; in vivo; inhibitor/antagonist; isoniazid; killings; latent infection; mouse model; osteogenic; pathogen; prevent; response; success; translational medicine; tuberculosis drugs; vaccine development

DESCRIPTION (provided by applicant): Tuberculosis (TB) kills 1-2 million people each year, making it the second leading cause of death due to an infectious agent. Almost 9 million TB patients are newly diagnosed each year, and half had latent TB infection (LTBI) prior to becoming sick. It is well known that LTBI bacilli are difficult to detect and difficult to treat. Many fundamental questions regarding LTBI are unanswered including: Where does virulent etiological agent of TB, Mycobacterium tuberculosis (M.tb) persist in vivo? How does M.tb persist when immunity or when antibiotics are present? How does M.tb leave the LTBI niche to cause reactivation TB? This latter unsolved question is particularly important for the understanding of the mechanisms by which reactivation occurs during co-infection with HIV. This project will address these important questions focusing primarily on the protection afforded by the newly described host cell for M.tb, the CD271+ bone marrow mesenchymal stem cell (BM-MSC). BMSCs are ideal cellular hosts for LTBI because these cells harbor poorly replicative M.tuberculosis; BMSC's lack antibacterial and immune activation functions; and BMSCs have membrane efflux pumps that may prevent antibiotics from acting on M.tb. The proposals are built on our results published early this year in Science Translational Medicine and on exciting unpublished data using the Cornell model of LTBI. The specific aims are: Aim 1. Define the mechanisms that protect M.tb in CD271+ BMSCs from immunity. Aim 2. Determine how M.tb in CD271+ BMSCs can be reactivated to cause active TB. Aim 3. Identify how CD271+ BMSCs protect M.tb from antibiotics. These studies are important because they address the following specific critical knowledge gaps: 1. Understanding of reactivation of LTBI in the context of a variety of immunossupressive scenarios including co-infection with HIV. 2. TB vaccine development, by defining mechanisms that contribute to M.tb's immune evasion. 3. TB drug development, by defining mechanisms that contribute to M.tb's drug evasion.

描述（由申请人提供）： 结核病每年导致1-2百万人死亡，使其成为传染性病原体导致的第二大死亡原因。每年新诊断出近900万结核病患者，其中一半在患病前有潜伏性结核病感染（LTBI）。众所周知，LTBI杆菌很难检测和治疗，许多关于LTBI的基本问题尚未得到解答，包括：结核病的致病性病原体结核分枝杆菌（M.tb）在体内的何处存在？当有免疫力或抗生素存在时，结核分枝杆菌是如何持续存在的？结核分枝杆菌如何离开LTBI生态位引起结核病复发？这后一个未解决的问题是特别重要的机制，通过它的重新激活发生在合并感染艾滋病毒的理解。本项目将解决这些重要问题，主要集中在新描述的结核分枝杆菌宿主细胞，CD 271+骨髓间充质干细胞（BM-MSC）提供的保护。BMSC是LTBI的理想细胞宿主，因为这些细胞具有复制性差的结核分枝杆菌; BMSC缺乏抗菌和免疫激活功能; BMSC具有可防止抗生素作用于结核分枝杆菌的膜外排泵。这些建议是基于我们今年早些时候发表在《科学转化医学》上的结果，以及使用康奈尔大学LTBI模型的令人兴奋的未发表数据。具体目标是：目标1。明确CD 271 + BMSCs中结核分枝杆菌免疫保护机制。目标2.确定CD 271 + BMSC中的结核分枝杆菌如何被重新激活以引起活动性结核病。目标3.确定CD 271 + BMSCs如何保护结核分枝杆菌免受抗生素的侵害。这些研究很重要，因为它们解决了以下具体的关键知识差距：1。了解LTBI在多种免疫抑制情况下（包括与HIV合并感染）的再激活。2.结核病疫苗的开发，通过确定机制，有助于结核分枝杆菌的免疫逃避。3.结核病药物开发，通过确定机制，有助于结核分枝杆菌的药物逃避。