Monocyte Biology and Biodefense

单核细胞生物学和生物防御

基本信息

批准号：
7023532
负责人：
Douglas Allen Drevets
金额：
$ 27.05万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2007-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7023532
关键词：
Listeria Listeria infections bacteria infection mechanism bioterrorism /chemical warfare bone marrow cell biology disease /disorder model host organism interaction inflammation intracellular intracellular parasitism laboratory mouse leukocyte activation /transformation monocyte

项目摘要

Monocytes are blood borne cells essential for effective innate and adaptive host defenses against infections with intracellular bacterial pathogens. Our laboratory and others identified sub-populations of blood monocytes in the mouse capable of functioning differentially as inflammatory or homeostatic cells. Remarkably, we found the same inflammatory monocytes that are recruited to infected tissues to kill Listeria monocytogenes (Lm) also are parasitized and transport intracellular Lm into the brain. Understanding why inflammatory monocytes that eventually become cytokine-activated effector cells are susceptible to intracellular parasitism is essential because most category A and B bacteria on the NIAID priority list are intracellular pathogens. The objective of this application is to establish the biological basis for parasitism of inflammatory monocytes during systemic infection with Lm, an intracellular pathogen relevant to biodefense. Our central hypothesis is that developmental immaturity prevents bone marrow monocytes and their precursors from responding optimally to cytokine activation to kill intracellular bacteria so that these cells are targeted for infection in the bone marrow then enter the circulation as infected monocytes. This hypothesis is based on our analysis of mouse monocyte sub-populations during systemic Lm infection and preliminary data showing parasitism of EP-MP12+CD11b+Ly-6Chi mononuclear cells in the bone marrow. This hypothesis will be tested with the following aims; 1) To elucidate the cellular basis of bone marrow parasitism during systemic Lm infection, 2) To elucidate why inflammatory monocytes are susceptible to parasitism by Lm, and 3) To determine from which organ infected monocytes enter the bloodstream. These aims will be accomplished using the well-established mouse model of Lm infection. This research is innovative because it applies the newly-recognized paradigm of monocyte heterogeneity in the mouse, to an established animal model of infection with an intracellular bacterium. Since human correlates of mouse monocyte sub-populations have been identified, our results will allow a better understanding than previously possible of how human monocytes function during the innate response to systemic infection. We expect that successful completion of these aims will reveal bone marrow to be an under-explored, but critical target organ for Lm , infection in vivo, and is the organ in which inflammatory monocytes are parasitized then emerge into the blood as Trojan horses. This will enable us to make clear key pathways of immunological activation of inflammatory monocytes manifested in vivo for killing intracellular bacteria in sub-lethal infection, but which are inadequate or dysfunctional during lethal disease. These data will then catalyze development of rational therapies to improve host defenses against severe and overwhelming infection by category A and B intracellular bacterial pathogens.

单核细胞是有效先天必不可少的血液传播细胞以及针对细胞内细菌病原体感染的自适应宿主防御。我们的实验室和其他实验室确定了小鼠中血细胞的亚群，能够作为炎症或稳态细胞差异功能。值得注意的是，我们发现募集到感染组织以杀死单核细胞增生李斯特菌（LM）的相同炎症单核细胞也被寄生，并将细胞内LM转运到大脑中。了解为什么最终变成细胞因子激活效应细胞的炎症单核细胞易受细胞内寄生虫的影响是必不可少的，因为NIAID优先级列表上大多数A类A和B细菌都是细胞内病原体。该应用的目的是建立与LM全身感染期间炎症单核细胞寄生虫的生物学基础，LM是一种与生物粘剂相关的细胞内病原体。我们的核心假设是，发育不成熟可防止骨髓单核细胞及其前体对细胞因子活化的最佳反应以杀死细胞内细菌，从而使这些细胞针对感染。然后，骨髓作为感染的单核细胞进入循环。该假设基于我们对全身性LM感染过程中小鼠单核细胞亚群的分析以及骨髓中EP-MP12+CD11b+LY-6CHI单核细胞的寄生虫的初步数据。该假设将以以下目的进行检验； 1）阐明系统性LM感染期间骨髓寄生虫的细胞基础，2）阐明为什么炎症单核细胞易于寄生，而LM易受寄生的影响，而3）以确定从哪些器官感染的单核细胞进入血液中。这些目标将使用良好的LM感染小鼠模型来实现。这研究之所以创新，是因为它应用了小鼠中新认可的单核细胞异质性的范式，并将其用于具有细胞内细菌的既定动物感染模型。由于已经确定了小鼠单核细胞亚群的人类相关性，因此我们的结果将使人类单核细胞在对系统感染的先天反应期间的功能比以前更具理解。我们预计，这些目标的成功完成将表明骨髓将是一个未经探索的骨髓，但对LM，体内感染感染的关键靶器官，并且是将炎性单核细胞寄生的器官，然后像特洛伊木马一样流向血液。这将使我们能够在体内明确的炎症单核细胞免疫激活的关键途径，该炎症是在体内表现出的，用于杀死细胞内致死感染中的细胞内细菌，但在致命性疾病期间不充分或功能障碍。然后，这些数据将催化理性疗法的发展，以改善A和B类细胞内细菌病原体对严重和压倒性感染的宿主防御能力。