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）： 肺结核（TB）每年造成1-200万人丧生，使其成为传染病患者导致死亡的第二大原因。每年将近900万结核病患者被新诊断出来，一半的患者在生病之前患有潜在的结核病感染（LTBI）。众所周知，LTBI细菌很难检测到难以治疗。关于LTBI的许多基本问题未得到答复：TB，结核分枝杆菌（M.TB）在体内持续存在有毒的病因学药物（M.TB）在哪里？当免疫或抗生素存在时，M.TB如何持续？ M.TB如何使LTBI生态位引起重新激活结核？后一个未解决的问题对于理解与HIV共同感染期间重新激活的机制尤为重要。该项目将解决这些重要问题，主要介绍了新描述的宿主细胞为M.TB，CD271+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，因为这些细胞具有较差的复制性大麻结核病。 BMSC缺乏抗菌和免疫激活功能； BMSC的膜外排泵可能会阻止抗生素在M.TB上起作用。这些建议是建立在我们今年年初在科学转化医学领域和使用LTBI的Cornell模型的令人兴奋的未发表数据的结果的基础上建立的。具体目的是：AIM 1。定义保护CD271+ BMSC中M.TB免疫力的机制。 AIM 2。确定CD271+ BMSC中的M.TB如何重新激活以引起活性TB。目标3。确定CD271+ BMSC如何保护M.TB免受抗生素的影响。这些研究之所以重要，是因为它们解决了以下特定的临界知识差距：1。在包括与HIV共同感染在内的各种免疫性场景的情况下，了解LTBI的重新激活。 2。通过定义有助于M.TB免疫逃避的机制，结核病疫苗的发展。 3. TB药物开发，通过定义有助于M.TB逃避药物的机制。