How S. aureus protein SSL11 inhibits neutrophil migration

据估计，美国每年有5万人感染金黄色葡萄球菌相关性肺炎。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菌之一。由于抗生素耐药性的流行和缺乏有效的疫苗，金黄色葡萄球菌肺炎的死亡率很高。继发感染大约有10%至30%发生在住院的重症新冠肺炎患者中，其中ICU环境中的继发感染频率要高得多。一份病例报告证实了这一点，该病例报告称，一名没有潜在疾病的年轻人感染了SARS-CoV-2和MRSA混合感染，并伴有严重肺炎。与其他细菌病原体不同，金黄色葡萄球菌约占人类人口的30%。虽然金黄色葡萄球菌定植与金黄色葡萄球菌临床感染的风险较高相关，但大多数被定植的人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致病机制之间转换仍不清楚。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，或者过度热情的中性粒细胞可能会导致组织损伤，导致肺炎。因此，了解金黄色葡萄球菌保持肺中性粒细胞静止的机制对于破译金黄色葡萄球菌如何保持其沉默的定植状态以及它的存在何时/如何致病至关重要。金黄色葡萄球菌超抗原样蛋白(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通过诱导细胞黏附来介导中性粒细胞的运动停滞。我们的初步研究表明，SSL11与重组整合素和整合素阻断抗体相互作用，抑制了SSL11诱导的细胞黏附和运动停滞。本研究的主要目标是：确定SSL11如何通过整合素诱导细胞黏附(目标1)；探索设计SSL11衍生的多肽以抑制与大量中性粒细胞渗透相关的肺炎的能力(目标2)。这项研究的结果将揭示细菌毒素作用于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/维持宿主定植提供洞察力，并将提供一种潜在的治疗肺炎的新方法。

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.