Calprotectin modulates neutrophil function during Staphylococcus aureus infection of the heart

钙卫蛋白在心脏金黄色葡萄球菌感染期间调节中性粒细胞功能

• 批准号: 10573312
• 负责人: Eric P Skaar
• 金额: $ 25.95万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573312
• 关键词: Address; Affect; Automobile Driving; Bacterial Endocarditis; Biological; Biology; Calcium; Cardiac Myocytes; Cells; Centers for Disease Control and Prevention (U.S.); Cytoplasmic Granules; Cytoplasmic Protein; Data; Direct Costs; Disease; Disease Outcome; Environment; Exhibits; Genetic; Genus Hippocampus; Heart; Heterodimerization; Homeostasis; Hospitalization; Immune; Immunologics; Inductively Coupled Plasma Mass Spectrometry; Infection; Inflammation; Inflammatory; Innate Immune Response; Iron; Leukocyte L1 Antigen Complex; Liquid substance; Liver; Manganese; Metabolic; Metals; Mitochondria; Molecular; Mus; Myelogenous; Nutrient; Nutritional Immunity; Organ; Phagosomes; Physiology; Play; Population; Process; Production; Protein Secretion; Proteins; Publishing; Reactive Oxygen Species; Reporting; Resolution; Respiration; Role; S100A8 gene; S100A9 gene; Site; Staphylococcus aureus; Staphylococcus aureus infection; Superoxides; Surface; Technology; Testing; Therapeutic; United States; Zinc; antimicrobial; cost estimate; design; experimental study; extracellular; fluorescence imaging; global health; insight; mass spectrometric imaging; methicillin resistant Staphylococcus aureus; mitochondrial metabolism; neutrophil; pathogen; response; suicidal; therapeutic target

PROJECT SUMMARY In 2019, methicillin-resistant Staphylococcus aureus infections were the basis of nearly 400,000 hospitalizations per year with direct costs estimated at $1.7 billion. Furthermore, S. aureus is the leading cause of bacterial endocarditis. Understanding host-pathogen interactions that skew disease outcome will facilitate the design of efficacious therapeutic strategies. Neutrophils possess antimicrobial functions that are critical to the innate immune response to S. aureus. Preliminary data show that neutrophils lacking calprotectin (CP), a highly abundant immune protein expressed by neutrophils, exhibit altered mitochondrial homeostasis, where CP- deficient neutrophils produce more mitochondrial superoxide in response to S. aureus compared to wild-type neutrophils. As a result, CP-deficient neutrophils undergo elevated suicidal NETosis. In addition, increased suicidal NETosis correlates with CP-deficient mice having lower bacterial burdens specifically within the heart and increased survival during systemic S. aureus infection. This suggests that neutrophil and CP biology is unique within the heart. Aim 1 will identify why the heart offers a unique niche for CP biology during S. aureus infection. More specifically, we will address (i) whether cardiomyocyte function in CP-deficient mice is altered, thereby skewing the neutrophil response and (ii) identify factors driving CP secretion/retention by neutrophils during infection in the heart. These experiments are significant as they define the immunological and metabolic environment of the heart, compared to other sites of infection, and the implications this has on CP and neutrophil biology. Aim 2 will focus on the role of intracellular CP in altering mitochondrial homeostasis. We will specifically test the role of CP in regulating mitochondrial metabolism and metal homeostasis, and downstream impacts this has on neutrophil function. These experiments are significant because they identify CP as a molecular rheostat for neutrophil function by controlling mitochondrial homeostasis, which may be broadly applicable to other cells expressing CP during inflammation. This proposal provides critical scientific insights into the function of CP that may be especially efficacious as a biological target for treating S. aureus infections of the heart. In addition, the technological advancements achieved by this proposal will create a platform that can be applied to other inflammatory diseases.

项目摘要 2019年，耐甲氧西林金黄色葡萄球菌感染是近40万例住院的基础 直接费用估计为17亿美元。此外，S.金黄色葡萄球菌是导致细菌感染的主要原因 心内膜炎了解宿主-病原体相互作用，扭曲疾病的结果将有助于设计 有效的治疗策略。中性粒细胞具有抗微生物功能，这对先天性 免疫应答金黄色。初步数据显示，缺乏钙卫蛋白（CP）的中性粒细胞， 由中性粒细胞表达的丰富的免疫蛋白，表现出改变的线粒体稳态，其中CP- 缺陷型中性粒细胞对S.金黄色葡萄球菌与野生型相比 中性粒细胞因此，CP缺陷型中性粒细胞的自杀性NETosis升高。此外，增加 自杀性NETosis与CP缺陷小鼠具有较低的细菌负荷相关，特别是在心脏内 并在全身性S.金黄色葡萄球菌感染。这表明中性粒细胞和CP生物学是 在心中独一无二。目的1将确定为什么心脏提供了一个独特的生态位CP生物学在S。金黄色 感染更具体地说，我们将解决（i）CP缺陷小鼠的心肌细胞功能是否改变， 从而扭曲中性粒细胞反应;（ii）识别驱动中性粒细胞CP分泌/保留的因素 在心脏感染期间。这些实验是重要的，因为它们定义了免疫和代谢 与其他感染部位相比，心脏的环境，以及这对CP和中性粒细胞的影响 生物学目的2将集中在细胞内CP在改变线粒体内稳态中的作用。我们将特别 测试CP在调节线粒体代谢和金属稳态中的作用，以及下游对此的影响。 对中性粒细胞功能有影响。这些实验是有意义的，因为他们确定CP作为一个分子变阻器 通过控制线粒体稳态来控制中性粒细胞功能，这可能广泛适用于其他细胞 在炎症过程中表达CP。这一提议为CP的功能提供了重要的科学见解， 作为治疗S的生物学靶点可能特别有效。心脏的金黄色葡萄球菌感染此外该 这项提案所取得的技术进步将创造一个平台，可以应用于其他 炎症性疾病。