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

描述(由申请人提供)： 结核病(TB)每年导致100-200万人死亡，成为第二大传染病致死原因。每年有近900万结核病患者被新诊断，其中一半人在患病前有潜伏的结核病感染(LTBI)。众所周知，LTBI杆菌很难发现，也很难治疗。关于LTBI的许多基本问题尚未得到解答，包括：结核病的致病毒力病原体结核分枝杆菌(M.tb)在体内持续存在的地方？结核分枝杆菌如何在免疫或抗生素存在的情况下持续存在？结核分枝杆菌是如何离开LTBI生态位而导致重新激活结核病的？后一个悬而未决的问题对于理解在与艾滋病毒共同感染期间重新激活的机制尤为重要。这个项目将解决这些重要的问题，主要集中在最新描述的结核分枝杆菌宿主细胞-CD271+骨髓间充质干细胞(BM-MSC)提供的保护。BMSCs是LTBI的理想细胞宿主，因为这些细胞含有复制能力较差的结核分枝杆菌；BMSC缺乏抗菌和免疫激活功能；BMSCs有可能阻止抗生素作用于结核分枝杆菌的膜外排泵。这些建议建立在我们今年早些时候发表在《科学转化医学》上的结果和使用康奈尔LTBI模型的令人兴奋的未发表数据的基础上。目的：1.明确CD271+BMSCs中结核分枝杆菌的免疫保护机制。目的2.确定CD271+骨髓间充质干细胞中的结核分枝杆菌如何被重新激活以导致活动性结核病。目的3.鉴定CD271+BMSCs对结核分枝杆菌抗生素的保护作用。这些研究很重要，因为它们解决了以下具体的关键知识空白：1.在各种免疫抑制方案的背景下，包括与艾滋病毒合并感染的情况下，理解LTBI的重新激活。2.结核病疫苗的开发，通过定义有助于结核分枝杆菌免疫逃避的机制。3.结核病药物开发，通过确定有助于结核分枝杆菌逃避药物的机制。

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 The proposals are built on our results published early this year in Science Translational Medicine and on exciting unpublished data using the Cornell model of LTBI.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.