How S. aureus protein SSL11 inhibits neutrophil migration

在美国，金黄色葡萄球菌相关肺炎估计每年造成5万例葡萄球菌感染。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。由于普遍存在抗生素耐药性和缺乏有效疫苗，金黄色葡萄球菌肺炎的死亡率很高。在住院的COVID-19重症患者中，继发感染发生率约为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，一名没有基础疾病的年轻男子通过了SARS-Cov-2和MRSA合并感染并严重肺炎。与其他细菌病原体不同，金黄色葡萄球菌在大约30%的人口中定居。虽然金黄色葡萄球菌定植与金黄色葡萄球菌临床感染的高风险相关，但大多数定植的个体不会经历金黄色葡萄球菌感染。金黄色葡萄球菌如何在定植和发病之间转变仍不清楚。在肺部感染期间，中性粒细胞的涌入是一把双刃剑：中性粒细胞清除入侵的病原体或过度的中性粒细胞可能引起组织损伤导致肺炎。因此，了解金黄色葡萄球菌使肺中性粒细胞处于静止状态的机制对于解释金黄色葡萄球菌如何维持其沉默的定植状态以及它的存在何时/如何成为致病性至关重要。葡萄球菌超级抗原样蛋白（SSL）家族是金黄色葡萄球菌复杂免疫逃避系统的一个例子。最近，我们报道了SSL11通过诱导细胞粘附介导人中性粒细胞的运动阻滞。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阻滞。本研究的主要目标是：确定SSL11如何通过整合素诱导细胞粘附（目的1）；探索设计ssl衍生肽抑制大量中性粒细胞浸润相关肺炎（如肺炎）的能力（目的2）。这项研究的结果将揭示细菌毒素作用逃避中性粒细胞功能的新机制，将为金黄色葡萄球菌如何建立/维持宿主定植提供见解，并将为治疗肺炎提供潜在的新疗法。

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.