Interaction of Human Pulmonary Macrophage and Dendritic Cell Subsets with Cryptococcus neoformans

每年约有225，000名艾滋病患者发生新型隐球菌脑膜炎， 每年有超过18.1万人死亡C.新生菌是一种吸入的机会性真菌病原体， 随后逃离肺部并传播到中枢神经系统， 发生脑膜炎。宿主因素决定C.新形动物最初生存或被摧毁， 肺吞噬细胞的定义仍然不清楚，这是理解这种病原体如何 最终导致脑膜炎和死亡。推测C.新生儿利用巨噬细胞从 肺转移到大脑导致脑膜炎然而，C.在某些巨噬细胞中可以杀死新生儿， 复制在其他人身上。此外，我们和其他人已经表明，树突状细胞（DCs），一种关键的先天性吞噬细胞， 可以吞噬并摧毁C.新生儿，但像巨噬细胞，这可能仅限于一个子集， 区议会我们的初步数据表明，原代人肺巨噬细胞和树突状细胞的亚群与C。 新型球菌，并表现出不同的抗隐球菌活性。一些先天吞噬细胞亚群杀死C。 而其他人则没有。因此，我们假设肺内的先天性吞噬细胞亚群 可以限制C。通过直接细胞内杀真菌活性的新形式生长， DC和巨噬细胞的容许亚群。我们将监测和表征的杀真菌反应 人肺吞噬细胞亚群与C.然后检查杀菌活性介质的作用 (iNOS、ROS和溶酶体酶组织蛋白酶B）。接下来，我们将区分 调节基因和信号通路可能协调杀真菌活性的每个子集， 与C. neoformans（Aim 2）。因此，我们的研究将确定吞噬细胞亚群负责 抗隐球菌活性或允许真菌生长，并确定宿主基因和信号通路， 可能负责调节这些反应。

Cryptococcus neoformans meningitis occurs in approximately 225,000 individuals with AIDS each year, resulting in over 181,000 annual deaths. C. neoformans is an opportunisitic fungal pathogen that is inhaled and subsequently escapes the lungs and disseminates to the central nervous system where life-threatening meningitis occurs. Host factors that determine whether C. neoformans initially survives or is destroyed by pulmonary phagocytes remain poorly defined, presenting a major gap in understanding how this pathogen ultimately causes meningitis and death. It is postulated that C. neoformans uses macrophages for transport from the lung to the brain to cause meningitis. However, C. neoformans can be killed in some macrophages but replicates in others. In addition, we and others have shown that dendritic cells (DCs), a critical innate phagocyte in the lung, can engulf and destroy C. neoformans, but like macrophages this may be restricted to a subset of DCs. Our preliminary data indicate subsets of primary human pulmonary macrophages and DCs interact with C. neoformans and exhibit differential anti-cyptococcal activities. Some innate phagocyte subsets kill C. neoformans, and others do not. Therefore, we hypothesize that subsets of innate phagocytes in the lung are capable of restricting C. neoformans growth through direct intracellular fungicidal activity absent in permissive subsets of DCs and macrophages. We will monitor and characterize the fungicidal response of human pulmonary phagocyte subsets to C. neoformans and then examine roles of mediators of fungicidal activity (iNOS, ROS, and lysosomal enzyme cathepsin B) in each subset (Aim 1). Next, we will identify differentially regulated genes and signaling pathways that may coordinate fungicidal activity in each subset following interaction with C. neoformans (Aim 2). Consequently, our studies will identify phagocyte subsets responsible for anti-cryptocccal activity or permissive fungal growth and identify the host genes and signaling pathways that may be responsible for regulating these responses.