Interaction Of Pathogenic Bacteria/Phagocytic Leukocytes

病原菌/吞噬白细胞的相互作用

• 批准号: 7196690
• 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/7196690
• 关键词: Staphylococcus aureus; Streptococcus pyogenes; apoptosis; bacteria infection mechanism; bacterial antigens; bacterial cytopathogenic effect; bacterial genetics; bactericidal immunity; chronic granulomatous disease; flow cytometry; gene expression; gene expression profiling; genetic regulation; host organism interaction; human genetic material tag; human tissue; immune response; immunogenetics; immunoregulation; inflammation; laboratory mouse; microarray technology; neutrophil; phagocytosis; proteomics; scanning electron microscopy

Human polymorphonuclear leukocytes (PMNs or neutrophils) are essential to the innate immune response against invading microorganisms. In contrast to the acquired immune response, which is dependent on previous interaction with specific bacteria, the ability of PMNs to kill microorganisms is immediate and non-specific. Inasmuch as PMNs produce highly toxic microbicidal components, moderation of infection-induced inflammation is critical for limiting host tissue destruction. This moderation is especially important given that PMNs are the predominant immune cell in most bacterial infections. A key aspect of our research investigates how PMNs ingest and kill bacteria, and elucidates post-phagocytosis sequelae such as apoptosis, processes crucial for the resolution phase of inflammation. Thus, one of our research objectives is to elucidate molecular processes in human PMNs that facilitate resolution of infection. To that end, we used genomics methodologies to establish a global model of host cell-pathogen interaction that provides fundamental insight into the resolution of infection in humans. A second focus of research in my laboratory investigates how bacterial pathogens such as Staphylococcus aureus and Streptococcus pyogenes (group A Streptococcus or GAS) evade human innate host defense to cause disease. Although most bacteria are killed readily by PMNs, some human pathogens have evolved mechanisms to inhibit phagocytosis and death resulting from exposure to ROS and microbicidal products. For example, strains of S. aureus which produce Panton-Valentine leukocidin cause lethal necrotizing pneumonia in non-immunocomprimised individuals, the molecular basis for which is unknown. We hypothesize staphylococcal pathogenesis includes evasion of PMN killing and undetermined host-susceptibility factors. GAS successfully evades PMN phagocytosis and killing to cause human infections such as pharyngitis and necrotizing fasciitis (flesh-eating syndrome). To date, our studies include identification of genes and proteins used by S. aureus and GAS to evade destruction by human neutrophils, hence contributing to virulence, survival and pathogenesis.

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。获得性免疫反应依赖于先前与特定细菌的相互作用，与此相反，PMN 杀死微生物的能力是立即且非特异性的。由于中性粒细胞产生剧毒的杀菌成分，缓和感染引起的炎症对于限制宿主组织破坏至关重要。鉴于中性粒细胞是大多数细菌感染中的主要免疫细胞，这种调节尤为重要。我们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，并阐明吞噬作用后遗症，例如细胞凋亡，这是炎症消退阶段的关键过程。因此，我们的研究目标之一是阐明人类中性粒细胞中促进感染解决的分子过程。为此，我们使用基因组学方法建立了宿主细胞-病原体相互作用的全局模型，为人类感染的解决提供了基本的见解。 我实验室的第二个研究重点是研究金黄色葡萄球菌和化脓性链球菌（A 组链球菌或 GAS）等细菌病原体如何逃避人类先天宿主防御而导致疾病。尽管大多数细菌很容易被 PMN 杀死，但一些人类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，产生潘顿-瓦伦丁杀白细胞素的金黄色葡萄球菌菌株会在非免疫功能低下的个体中引起致命性坏死性肺炎，其分子基础尚不清楚。我们假设葡萄球菌发病机制包括逃避中性粒细胞杀伤和未确定的宿主易感因素。 GAS成功地逃避了PMN的吞噬和杀伤，导致人类感染，如咽炎和坏死性筋膜炎（食肉综合症）。迄今为止，我们的研究包括鉴定金黄色葡萄球菌和 GAS 用于逃避人类中性粒细胞破坏的基因和蛋白质，从而有助于毒力、生存和发病机制。