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）对于对侵入微生物的先天免疫反应至关重要。与获得的免疫反应相反，该免疫反应取决于先前与特定细菌的相互作用，PMN杀死微生物的能力是直接且非特异性的。由于PMN会产生剧毒毒性成分，因此感染诱导的炎症的适度对于限制宿主组织破坏至关重要。鉴于PMN在大多数细菌感染中是主要的免疫细胞，因此这种适度尤为重要。我们研究的一个关键方面调查了PMN如何摄入和杀死细菌，并阐明了示例性后遗症，例如凋亡，对炎症的分辨率阶段至关重要。因此，我们的研究目标之一是阐明促进感染分辨率的人类PMN中的分子过程。为此，我们使用基因组学方法来建立一种全球宿主细胞病原相互作用模型，该模型为人类感染的分辨率提供了基本的见解。 我的实验室中的第二个研究重点调查了细菌病原体（例如金黄色葡萄球菌和链球菌链球菌或气体）如何逃避人类先天宿主防御以引起疾病。尽管大多数细菌很容易被PMN杀死，但一些人类病原体具有抑制吞噬作用的机制，并导致暴露于ROS和杀菌产物导致死亡。例如，产生panton-valentine白细胞素的金黄色葡萄球菌菌株会在非免疫原子化个体中引起致命性坏死性肺炎，这是未知的分子基础。我们假设葡萄球菌发病机理包括逃避PMN杀伤和未确定的宿主敏感性因子。气体成功地逃避了PMN吞噬作用并杀死，引起人类感染，例如咽炎和坏死性筋膜炎（肉种综合征）。迄今为止，我们的研究包括金黄色葡萄球菌和气体使用的基因和蛋白质的鉴定，以避免人类中性粒细胞破坏破坏，从而有助于毒力，生存和发病机理。