How S. aureus protein SSL11 inhibits neutrophil migration

金黄色葡萄球菌蛋白 SSL11 如何抑制中性粒细胞迁移

• 批准号: 10588217
• 负责人: Chen Chen
• 金额: $ 25.69万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-02 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10588217
• 关键词: 2019-nCoV; Antibiotic Resistance; Antigen-Antibody Complex; Bacterial Toxins; Biology; Blocking Antibodies; COVID-19 patient; Case Study; Cell Adhesion; Clinical; Disease; Engineering; Environment; Etiology; Frequencies; Genus staphylococcus; Goals; Hospitalization; Human; Immune Evasion; Individual; Infection; Integrins; Intensive Care; Invaded; Lung; Lung infections; Mediating; Neutrophil Infiltration; Outcome Study; Pathogenesis; Pathogenicity; Peptides; Pneumonia; Population; Prevalence; Protein Family; Proteins; Recombinants; Reporting; Rest; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus aureus infection; Superantigens; System; Tissues; United States; Vaccines; cell motility; co-infection; high risk; host colonization; inhibiting antibody; insight; methicillin resistant Staphylococcus aureus; migration; mortality; neutrophil; novel therapeutics; pathogen; pathogenic bacteria; secondary infection; ventilator-associated pneumonia; young man

S. aureus associated pneumonia accounts for an estimated 50,000 staphylococcal infections per year in the United States. S. aureus is one of the leading etiologic agents of ventilator-associated pneumonia in the intensive care environment. S. aureus pneumonia has a high rate of mortality due to the prevalence of antibiotic resistance and lack of an effective vaccine. Secondary infections occur in approximately 10% to 30% of cases in hospitalized, severely ill COVID-19 patients, with much greater frequency in the ICU setting. This is confirmed by a case report that a young man without underlying conditions passed a with SARS-Cov-2 and MRSA co-infection with severe pneumonia. Unlike other bacterial pathogens, S. aureus colonizes about 30% of the human population. Although S. aureus colonization is associated with higher risks for S. aureus clinical infections, most colonized individuals will not experience S. aureus infections. How S. aureus transitions between colonization and pathogenesis remain unclear. During pulmonary infection, the neutrophil influx is a double-edged sword: neutrophils clear the invading pathogens or overzealous neutrophils may cause tissue damage leading to pneumonia. Hence, understanding the mechanisms by which S. aureus keeps lung neutrophils at rest is crucial to decipher how S. aureus maintains its silent colonization state and when/how its presence becomes pathogenic. The Staphylococcal Superantigen-Like protein (SSL) family is an example of a complex immune evasion system of S. aureus. Recently, we reported that SSL11 mediates motility arrest in human neutrophils by inducing cell adhesion. Our preliminary study showed that SSL11 interacted with recombinant integrins and integrins blocking antibodies inhibited SSL11 induced cell adhesion and motility arrest. The main goals of this study are: To determine how SSL11 induces cell adhesion via integrins (aim 1); To explore the ability to engineer the SSL-derived peptides to inhibit pneumonia associated with massive neutrophil infiltration such as pneumonia (aim 2). The outcomes of this study will shed light on a new mechanism of bacterial toxin action to evade neutrophil function, will provide insight into how S. aureus establishes/maintains host colonization, and will provide a potential new therapy against pneumonia.

S.在美国，金黄色葡萄球菌相关的肺炎估计每年造成50，000例葡萄球菌感染。S.金黄色葡萄球菌是重症监护环境中呼吸机相关性肺炎的主要病原体之一。S.由于抗生素耐药性的普遍存在和缺乏有效的疫苗，金黄色葡萄球菌肺炎具有高死亡率。在住院的重症COVID-19患者中，继发性感染发生率约为10%至30%，在ICU环境中的发生率要高得多。一份病例报告证实了这一点，该报告称，一名没有基础疾病的年轻男子通过了SARS-Cov-2和MRSA合并感染的严重肺炎。与其他细菌病原体不同，S.金黄色葡萄球菌在大约30%的人类群体中定殖。虽然S.金黄色葡萄球菌定植与S.金黄色葡萄球菌临床感染，大多数定殖个体不会经历S.金黄色葡萄球菌感染如何S。金黄色葡萄球菌在定植和发病机制之间的转变仍不清楚。在肺部感染期间，中性粒细胞内流是一把双刃剑：中性粒细胞清除入侵的病原体，或者过度热心的中性粒细胞可能引起组织损伤，导致肺炎。因此，了解S。金黄色葡萄球菌使肺中性粒细胞处于静止状态，这对于解释S。金黄色葡萄球菌保持其沉默的定殖状态以及其存在何时/如何变成致病性。葡萄球菌超抗原样蛋白（SSL）家族是葡萄球菌复杂免疫逃避系统的一个例子。金黄色。最近，我们报道了SSL11通过诱导细胞粘附来介导人中性粒细胞的运动停滞。我们的初步研究表明，SSL11与重组整合素相互作用，整合素阻断抗体抑制SSL11诱导的细胞粘附和运动停滞。本研究的主要目的是：确定SSL11如何通过整合素诱导细胞粘附（目的1）;探索工程化SSL衍生肽抑制与大量中性粒细胞浸润相关的肺炎（如肺炎）的能力（目的2）。这项研究的结果将揭示一种新的细菌毒素作用机制，以逃避中性粒细胞的功能，将提供洞察如何S。金黄色葡萄球菌建立/维持宿主定殖，并且将提供针对肺炎的潜在新疗法。