Interaction Of Pathogenic Bacteria With Human Phagocytic

人类多形核白细胞（PMN或中性粒细胞）是对抗入侵微生物的先天免疫应答所必需的。与获得性免疫应答不同，获得性免疫应答需要时间来发展，并且依赖于先前与特定病原体的相互作用，中性粒细胞摄取和杀死感染性微生物的能力是立即的、非特异性的，并且不依赖于先前的病原体暴露。我的实验室研究人类中性粒细胞与细菌病原体的相互作用。该研究的一个关键方面是研究中性粒细胞如何摄取和杀死细菌，并阐明吞噬后的后遗症，如程序性细胞死亡，这是解决感染所必需的过程。值得注意的是，我们发现了一个遗传程序，该程序将人类PMN中细菌病原体的吞噬作用与程序性细胞死亡（凋亡）联系起来，使用尖端的微阵列技术筛选数千个人类基因。 虽然大多数人类病原体很容易被中性粒细胞杀死，但有些已经进化出抑制吞噬作用和暴露于ROS和杀微生物产物导致死亡的机制。例如，化脓性链球菌（A组链球菌或GAS）成功地逃避了PMN的吞噬作用和杀伤作用，导致人类感染，如咽炎、蜂窝织炎和坏死性筋膜炎（食肉综合征）。这些感染和感染后后遗症是全球高发病率和死亡率的原因。我实验室的第二个研究重点是研究细菌病原体如GAS如何逃避PMN的杀伤而引起疾病。使用DNA微阵列，我们发现了GAS用于逃避PMN吞噬和杀伤的全基因组保护性反应。在这些研究中，我们确定了349个GAS基因，在吞噬细胞与人中性粒细胞的相互作用过程中差异调节。我们发现11种新的GAS分泌蛋白在PMN吞噬过程中上调，并发现以前未表征的双组分基因调控系统有助于免疫逃避，以促进GAS存活并导致人类疾病。

Human polymorphonuclear leukocytes (PMNs or neutrophils) are essential to the innate immune response against invading microorganisms. In contrast to the acquired immune response, which requires time to develop and is dependent on previous interaction with specific pathogens, the ability of PMNs to ingest and kill infectious microorganisms is immediate, non-specific, and not dependent on previous pathogen exposure. My laboratory studies the interaction of human PMNs with bacterial pathogens. A key aspect of the research investigates how PMNs ingest and kill bacteria, and elucidates post-phagocytosis sequelae such as programmed cell death, processes essential for the resolution of infection. Notably, we discovered a genetic program that links phagocytosis of bacterial pathogens in human PMNs with programmed cell death (apoptosis) using cutting edge microarray technology to screen thousands of human genes. Although most human pathogens are killed readily by PMNs, some have evolved mechanisms to inhibit phagocytosis and death resulting from exposure to ROS and microbicidal products. For example, Streptococcus pyogenes (Group A Streptococcus or GAS) successfully evades PMN phagocytosis and killing to cause human infections such as pharyngitis, cellulitis, and necrotizing fasciitis (flesh-eating syndrome). These infections and post-infection sequelae are responsible for high morbidity and mortality globally. A second focus of research in my laboratory investigates how bacterial pathogens such as GAS evade PMN killing to cause disease. Using DNA microarrays, we discovered a genome-wide protective response used by GAS to evade PMN phagocytosis and killing. In these studies, we identified 349 GAS genes that were differentially regulated during phagocytic interaction with human PMNs. We found that 11 novel GAS secreted proteins were up-regulated during PMN phagocytosis, and discovered that a previously uncharacterized two-component gene regulatory system facilitates immune evasion to promote GAS survival and cause disease in humans.