Interaction Of Pathogenic Bacteria With Human Phagocytic

致病菌与人类吞噬细胞的相互作用

• 批准号: 6809287
• 负责人: FRANK R DELEO
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6809287
• 关键词: CD antigens; Staphylococcus aureus; Streptococcus pyogenes; antigen receptors; apoptosis; bacterial cytopathogenic effect; bacterial genetics; bacterial proteins; bactericidal immunity; electron microscopy; flow cytometry; functional /structural genomics; gene induction /repression; host organism interaction; human tissue; laboratory mouse; microarray technology; microorganism culture; neutrophil; oligonucleotides; phagocytosis; polymerase chain reaction; proteomics

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.

人类多形核白细胞（PMN 或中性粒细胞）对于针对入侵微生物的先天免疫反应至关重要。获得性免疫反应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，与此相反，PMN 摄取和杀死传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调查中性粒细胞如何摄取和杀死细菌，并阐明吞噬后的后遗症，例如程序性细胞死亡，这是解决感染所必需的过程。值得注意的是，我们使用尖端微阵列技术筛选了数千个人类基因，发现了一种将人类中性粒细胞中细菌病原体的吞噬作用与程序性细胞死亡（细胞凋亡）联系起来的遗传程序。 尽管大多数人类病原体很容易被 PMN 杀死，但有些病原体已经进化出抑制吞噬作用和因暴露于 ROS 和杀菌产品而导致死亡的机制。例如，化脓性链球菌（A组链球菌或GAS）成功地逃避了PMN的吞噬和杀灭作用，引起人类感染，如咽炎、蜂窝织炎和坏死性筋膜炎（食肉综合症）。这些感染和感染后后遗症导致全球高发病率和死亡率。我实验室的第二个研究重点是调查 GAS 等细菌病原体如何逃避 PMN 杀灭而导致疾病。利用 DNA 微阵列，我们发现了 GAS 用来逃避 PMN 吞噬和杀伤的全基因组保护反应。在这些研究中，我们鉴定了 349 个 GAS 基因，这些基因在与人类 PMN 的吞噬相互作用过程中受到差异调节。我们发现 11 种新型 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利于免疫逃避，从而促进 GAS 存活并导致人类疾病。