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: 10464764
• 负责人: Eric P Skaar
• 金额: $ 21.63万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464764
• 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; Proteins; Publishing; Reactive Oxygen Species; Reporting; Resolution; Respiration; Role; S100A8 gene; S100A9 gene; Site; Staphylococcus aureus; Staphylococcus aureus infection; Superoxides; Surface; 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40万住院的基础 每年，直接成本估计为17亿美元。此外，金黄色葡萄球菌是细菌的主要原因 心内膜炎。了解伴侣疾病结局的宿主病原体相互作用将有助于设计 有效的治疗策略。中性粒细胞具有对先天性至关重要的抗菌功能 对金黄色葡萄球菌的免疫反应。初步数据表明，中性粒细胞缺乏钙骨蛋白（CP），这是一种高度 嗜中性粒细胞表达的丰富免疫蛋白表现出改变的线粒体稳态，其中CP- 与野生型相比 中性粒细胞。结果，CP缺乏的中性粒细胞经历了自杀脂肪的升高。另外，增加 自杀性Netosis与患有较低细菌负担的CP缺陷小鼠专门在心脏内部 并增加了全身性金黄色葡萄球菌感染期间的生存率。这表明中性粒细胞和CP生物学是 内心独特。 AIM 1将确定为什么心脏在金黄色葡萄球菌期间为CP生物学提供独特的利基市场 感染。更具体地说，我们将解决（i）CP缺陷小鼠中的心肌细胞功能是否改变， 从而使中性粒细胞反应偏斜，（ii）确定促进中性粒细胞CP分泌/保留的因素 心脏感染期间。这些实验很重要，因为它们定义了免疫学和代谢 与其他感染部位相比，心脏的环境以及对CP和中性粒细胞的影响 生物学。 AIM 2将集中于细胞内CP在改变线粒体稳态中的作用。我们将具体 测试CP在调节线粒体代谢和金属稳态中的作用，下游会影响这一点 具有中性粒细胞功能。这些实验很重要，因为它们将CP识别为分子变势 通过控制线粒体稳态来进行中性粒细胞功能，这可能广泛适用于其他细胞 在炎症期间表达CP。该建议提供了对CP功能的关键科学见解 作为治疗心脏链球菌感染的生物学靶标，可能特别有效。另外， 该提案实现的技术进步将创建一个可以应用于其他的平台 炎症性疾病。