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第一线，特别是由诸如沙门氏菌等生物体引起的感染。金黄色葡萄球菌（SA）。尽管有有效的PMN抗微生物系统，但10-20%的摄入SA在PMN中保持活力，但不复制。中性粒细胞内SA的持续存在具有深远的临床后果，因为葡萄球菌感染的特征是复发、转移和SA敏感的抗生素治疗失败。 在我们正在进行的关于SA负载的人PMN的命运及其与单核细胞衍生的巨噬细胞（MMCs）的相互作用的研究中，我们获得了几个新的发现：PMN-SA（1）在吞噬SA后的早期表现出病原体诱导的凋亡的非典型表型;（3）维持持续水平的增殖细胞核抗原（PCNA），一种在PMN胞质中表达的细胞周期蛋白，最近与通过清除半胱氨酸蛋白酶原延长PMN存活有关;和（4）以与坏死性凋亡最一致的方式裂解，坏死性凋亡是一种以前从未在PMN中描述过的不依赖半胱天冬酶的程序性坏死细胞死亡途径，但涉及多组分胞质信号复合物和对受体相互作用蛋白激酶1（RIP 1 K）的依赖。我们的理由是，这些细胞事件和之间的PMN-SA和MPEG4驱动SA感染的临床标志，并提出研究，探索我们的新观察的机制。目标1：确定由M？1A引起的PMN-SA胞饮失败的潜在机制：确定由PMN-SA产生的促进由M？1B引起的胞饮的信号：确定由PMN-SA产生的主动阻断由M？1C引起的胞饮的信号：确定由PMN-SA激发的M？1D的信号通路和效应器应答：确定由PMN-SA产生的外核体调节由M？1B引起的胞饮的作用目的2：确定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最初延长的存活和最终溶解的贡献2C：确定PMN-SA进行坏死性凋亡时参与的信号通路2D：确定TNF α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非典型凋亡、细胞凋亡失败和PMN-SA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。