Consequences of interactions between human neutrophils and Staphylococcus aureus

人类中性粒细胞和金黄色葡萄球菌之间相互作用的后果

• 批准号: 9230328
• 负责人: William M. Nauseef
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9230328
• 关键词: Affect; Alpha Cell; Antibiotic Therapy; Antibiotics; Apoptosis; Apoptotic; Biochemical; Biology; Caspase; Cell Cycle Proteins; Cell Death; Cells; Cessation of life; Clinical; Communities; Complex; Cytolysis; Cytoplasm; Cytoplasmic Granules; Data; Dependence; Disease; Environment; Epidemic; Equus caballus; Event; Exhibits; Experimental Models; Extensive Necrosis; Failure; Genus staphylococcus; Host Defense; Human; Immune; Individual; Infection; Inflammation; Inflammatory Response; Ingestion; Innate Immune System; Invaded; Link; Lung; Mediating; Membrane; Methicillin Resistance; Microbe; Molecular; Morbidity - disease rate; Mus; NADPH Oxidase; Necrosis; Neoplasm Metastasis; Organism; Oxidants; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Phenotype; Proliferating Cell Nuclear Antigen; Protein Kinase; Proteins; RIPK1 gene; Recruitment Activity; Regulation; Regulatory Pathway; Relapse; Role; Signal Pathway; Signal Transduction; Skin; Staphylococcal Infections; Staphylococcus aureus; Supportive care; System; TNF gene; Testing; Therapeutic Intervention; Tissues; Work; antimicrobial; base; cytokine; innovation; insight; macrophage; microbicide; microorganism; monocyte; mortality; neutrophil; new therapeutic target; novel; pathogen; public health relevance; response; therapeutic target

 DESCRIPTION (provided by applicant): Human polymorphonuclear leukocytes (PMN) are at the front-line of cellular innate immune-mediated host defense against infection, especially those caused by organisms such as S. aureus (SA). Despite the potent PMN antimicrobial system, 10-20% of ingested SA remained viable, but not replicating, in PMN. Persistence of SA within PMN has profound clinical consequences, as signature features of staphylococcal infection are relapse, metastases, and failure of antibiotics to which SA are susceptible. In our ongoing studies of the fate of SA-laden human PMN and their interactions with monocyte-derived macrophages (MØ), we have made several novel findings: PMN-SA (1) early after phagocytosis of SA display a phenotype that is atypical for pathogen-induced apoptosis; (2) are not efficiently efferocytosed by MØ; (3) maintain sustained levels of proliferating cell nuclear antigen (PCNA), a cell-cycle protein expressed in PMN cytoplasm, and recently linked to prolonging PMN survival by scavenging procaspases; and (4) lyse in a fashion most consistent with necroptosis, a caspase-independent programmed necrotic cell death pathway never previously described in PMN but involving a multicomponent cytoplasmic signaling complex and dependence on receptor-interacting protein kinase 1 (RIP1K). We reason that these cellular events in and between PMN-SA and MØ drive the clinical hallmarks of SA infection and propose studies to explore of the mechanisms underlying our novel observations. Aim 1: Determine the mechanisms underlying the failed efferocytosis of PMN-SA by M¿ 1A: Identify signals generated by PMN-SA that promote efferocytosis by MØ 1B: Identify signals generated by PMN-SA that actively block efferocytosis by MØ 1C: Identify signaling pathways and effector responses of MØ challenged with PMN-SA 1D: Determine the role of ectosomes generated by PMN-SA to modulate efferocytosis by MØ Aim 2: Identify cellular components, biochemical events, and signaling pathways underlying necroptosis of PMN-SA 2A: Determine the composition and regulation of the ripoptosome in PMN-SA 2B: Determine the contribution of PCNA to the initial prolonged survival and eventual lysis of PMN-SA 2C: Determine the signaling pathways engaged as PMN-SA proceed to necroptosis 2D: Determine the role of TNF-dependent signaling in necroptosis of PMN-SA Our studies will identify mechanisms responsible for the atypical apoptosis, failed efferocytosis, and necrotic death of PMN-SA, thereby providing novel insights into fundamental aspects of phagocyte control of the inflammatory response and new potential therapeutic targets.

 描述（由申请人提供）：人类多形核白细胞（PMN）处于细胞先天免疫介导的宿主防御感染的前线，尤其是由金黄色葡萄球菌（SA）等生物体引起的感染。尽管 PMN 抗菌系统有效，但摄入的 SA 在 PMN 中仍有 10-20% 的活性，但不能复制。 SA 在 PMN 中的持续存在具有深远的临床后果，因为葡萄球菌感染的标志性特征是复发、转移和 SA 敏感的抗生素失效。 在我们正在进行的关于携带 SA 的人类 PMN 的命运及其与单核细胞衍生的巨噬细胞 (MØ) 相互作用的研究中，我们取得了一些新的发现： PMN-SA (1) 在 SA 吞噬作用早期表现出一种对于病原体诱导的细胞凋亡而言非典型的表型； (2) 不能被 MØ 有效地胞吞； (3) 维持增殖细胞核抗原 (PCNA) 的持续水平，PCNA 是一种在 PMN 细胞质中表达的细胞周期蛋白，最近通过清除 procaspase 与延长 PMN 存活相关； (4) 以与坏死性凋亡最一致的方式裂解，坏死性凋亡是一种独立于半胱天冬酶的程序性坏死细胞死亡途径，以前从未在 PMN 中描述过，但涉及多组分细胞质信号复合物和对受体相互作用蛋白激酶 1 (RIP1K) 的依赖性。我们推断 PMN-SA 和 MØ 内部和之间的这些细胞事件驱动了 SA 感染的临床特征，并提出研究来探索我们新观察结果背后的机制。目标 1：确定 M¿ 1A 导致 PMN-SA 胞吞作用失败的机制：识别 PMN-SA 生成的促进 MØ 1B 胞吞作用的信号：识别 PMN-SA 生成的、主动阻止 MØ 1C 胞吞作用的信号：识别受到 PMN-SA 1D 攻击的 MØ 的信号通路和效应器反应：确定由 PMN-SA 1D 攻击的 MØ 产生的胞吐体的作用 PMN-SA 通过 MØ 调节胞吞作用 目标 2：识别 PMN-SA 坏死性凋亡的细胞成分、生化事件和信号通路 2A：确定 PMN-SA 中核糖体的组成和调节 2B：确定 PCNA 对 PMN-SA 最初延长存活和最终裂解的贡献 2C：确定参与的信号通路 PMN-SA 进行坏死性凋亡 2D：确定 TNFα 依赖性信号传导在 PMN-SA 坏死性凋亡中的作用我们的研究将确定导致 PMN-SA 的非典型凋亡、胞吞作用失败和坏死性死亡的机制，从而为吞噬细胞控制炎症反应的基本方面和新的潜在治疗靶点提供新的见解。