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: 9131612
• 负责人: William M. Nauseef
• 金额: $ 38万
• 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/9131612
• 关键词: Affect; Antibiotic Therapy; Antibiotics; Apoptosis; Apoptotic; Binding; Biochemical; Biology; Caspase; Cell Cycle Proteins; Cell Death; Cells; Cessation of life; Clinical; Clinical Data; Communities; Complex; Cytolysis; Cytoplasm; Cytoplasmic Granules; Data; Dependence; Disease; Environment; Epidemic; Equus caballus; Event; Exhibits; Experimental Models; Extensive Necrosis; Failure; Genus staphylococcus; Health; Host Defense; Human; Immune; Immune system; Individual; Infection; Inflammation; Inflammatory Response; Ingestion; Invaded; Link; Lung; Mediating; Membrane; 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; methicillin resistant Staphylococcus aureus; microbicide; microorganism; monocyte; mortality; neutrophil; novel; pathogen; programs; 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（由适用提供）：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，尤其是诸如金黄色葡萄球菌（SA）等生物引起的宿主防御。尽管有潜在的PMN抗菌系统，但在PMN中，摄入的SA中有10-20％的摄入量仍然可行，但不复制。 SA在PMN中的持久性具有深远的临床后果，因为葡萄球菌感染的特征是SA易感的抗生素的缓解，转移和抗生素失败。在我们正在进行的有关SA含SA的人PMN命运及其与单核细胞衍生巨噬细胞（Mø）的相互作用的研究中，我们已经做出了一些新颖的发现：SA吞噬吞噬后的PMN-SA（1）表现出一种表型，这是一种非典型的病原体诱导凋亡的表型； （2）没有有效的Mø有效； （3）维持持续水平的增殖细胞核抗原（PCNA），一种在PMN细胞质中表达的细胞周期蛋白，最近与通过清除promass酶的延长PMN存活有关； （4）以最终与坏死性的方式进行裂解，这是一种与caspase无关的坏死细胞死亡途径，以前从未在PMN中描述过，但涉及多组分的细胞质信号传导复杂的复杂并依赖受体相互作用的蛋白质激酶1（RIP1K）。我们认为，PMN-SA和Mø之间的这些细胞事件推动了SA感染和建议研究的临床标志，以探索我们新颖观察的基础机制。目标1：确定通过M€1A的失败PMN-SA胞吞作用的机制：识别由PMN-SA产生的信号，该信号通过Mø1B促进效率促进效率，确定PMN-SA产生的信号由PMN-SA产生的信号，该信号通过Mø1c通过Mø1C的效率来积极效率1C：确定pM N-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-s-pema wime to pm osia。通过MøAIM2：确定细胞成分，生化事件和信号通路PMN-SA 2A的坏死性潜在的信号通路：确定PMN-SA 2B中ripopoptosoms的组成和调控：确定PCNA对PCNA对初始延长的生存和最终ASA的贡献PMN-SA-SA-SA 2C的贡献，以下坏死2D：确定TNF信号传导在PMN-SA坏死中的作用，我们的研究将确定导致非典型凋亡，失败的递送症和PMN-SA的坏死死亡的机制，从而为潜在的范围响应的基本方面提供了针对疫苗控制的基本方面的新见解，并具有新的趋势控制措施。