Monocyte subsets and host defense

描述（由申请人提供）：本提案将研究传染病中的单核细胞异质性。我们已经确定了小鼠单核细胞亚群，它们在感染原生寄生虫利什曼原虫时表现非常不同。一个单核细胞亚群在L. major感染的反应中迅速从血液中动员起来，单核细胞迁移的机制似乎是这个单核细胞亚群所独有的。我们将这些快速迁移的细胞称为“效应”单核细胞，因为它们在杀死L. major寄生虫方面非常有效。我们将检查人类单核细胞亚群，并确定人类单核细胞亚群是否也是L. major和其他细胞内病原体的有效杀手。我们建议研究单核细胞杀伤的机制，并研究单核细胞呼吸爆发（NOX2）在寄生虫杀伤中的作用。与“效应”单核细胞相比，所谓的“经典”单核细胞群不能有效地杀死L. major。我们建议比较和对比这两个小鼠单核细胞亚群，然后确定人类单核细胞亚群是否同样容易受到细胞内感染。在目标3中，我们建议利用下一代RNA测序来比较L. major感染期间两个小鼠和三个人类单核细胞亚群的转录组。这些研究将有助于深入了解单核细胞对感染的反应的本质，以及寄生虫的转录变化如何与寄生虫的细胞内存活相关。这项工作将提供

DESCRIPTION (provided by applicant): This proposal will examine monocyte heterogeneity during infectious diseases. We have identified subsets of murine monocytes that behave very differently during infection with the protozoan parasite, Leishmania major. One monocyte subset is rapidly mobilized from the blood in response to L. major infection, and the mechanism of monocyte migration appears to be unique to this subset of monocytes. We have termed these rapidly migrating cells "effector" monocytes because they are remarkably efficient at killing L. major parasites. We will examine human monocyte subsets and determine whether a subset of human monocytes are also efficient killers of L. major and other intracellular pathogens. We propose to examine the mechanism(s) of monocyte killing, and examine the role of the monocyte respiratory burst (NOX2) in parasite killing. In contrast to the "effector" monocytes, the so-called "classical" monocyte population fails to efficiently kill L. major. We propose to compare and contrast these two subpopulations of murine monocytes, and then determine whether human monocyte subsets are similarly susceptible to intracellular infections. In aim 3, we propose to utilize next generation RNA sequencing to compare the transcriptomes of the two murine and three human monocyte subsets during infection with L. major. These studies should provide insight into the nature of the monocyte responses to infection, and how transcriptional changes in the parasite are correlated with parasite intracellular survival. This work will provide the first comparison of the major monocyte subsets and their responses to parasite invasion.