Monocyte Biology and Biodefense

单核细胞是有效的先天所必需的血液传播细胞。 以及适应性宿主防御细胞内细菌病原体的感染。我们的实验室和其他人在小鼠中发现了能够作为炎症细胞或稳态细胞发挥不同功能的血液单核细胞亚群。值得注意的是，我们发现同样的炎性单核细胞被招募到感染组织中以杀死单核细胞增生性李斯特菌(LM)，它们也被寄生并将细胞内的单核细胞输送到大脑中。了解为什么最终成为细胞因子激活的效应细胞的炎性单核细胞容易受到细胞内寄生的影响是至关重要的，因为NIAID优先名单上的大多数A和B类细菌都是细胞内病原体。该应用的目的是建立全身感染时炎性单核细胞寄生的生物学基础，LM是一种与生物防御相关的细胞内病原体。我们的中心假设是，发育不成熟阻止了骨髓单核细胞及其前体细胞对细胞因子激活的最佳反应，从而杀死细胞内细菌，从而使这些细胞成为感染的靶点。 然后，骨髓以受感染的单核细胞的形式进入循环。这一假设是基于我们对系统性LM感染过程中小鼠单核细胞亚群的分析，以及显示EP-MP12 CD11b Ly-6CHI单个核细胞在骨髓中寄生的初步数据。这一假说将以以下目的进行检验：1)阐明系统性LM感染时骨髓寄生的细胞学基础；2)阐明为什么炎性单核细胞容易受到LM的寄生；3)确定受感染的单核细胞从哪个器官进入血液。 这些目标将使用已建立的LM感染的小鼠模型来实现。这 这项研究具有创新性，因为它将新认识的小鼠单核细胞异质性范例应用于细胞内细菌感染的已建立的动物模型。由于人类与小鼠单核细胞亚群的相关性已经确定，我们的结果将使我们能够比以前更好地理解人类单核细胞在对系统性感染的先天反应中如何发挥作用。我们预计，这些目标的成功完成将揭示骨髓是在体内感染LM的一个未被充分探索的但关键的靶器官，并且是一个寄生炎性单核细胞然后以特洛伊木马的形式出现在血液中的器官。这将使我们能够明确体内表现的炎性单核细胞免疫激活的关键途径，以杀灭亚致死性感染中的细胞内细菌，但在致死性疾病中不充分或功能失调。这些数据将促进合理治疗的发展，以提高宿主对A和B类细胞内细菌病原体严重和压倒性感染的防御能力。

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.