The Fibrinogen-binding M1 Protein Reduces Pharyngeal Cell Adherence and Colonization Phenotypes of M1T1 Group A Streptococcus
The Fibrinogen-binding M1 Protein Reduces Pharyngeal Cell Adherence and Colonization Phenotypes of M1T1 Group A Streptococcus
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DOI：
10.1074/jbc.m113.529537
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发表时间：
2014-02-07
影响因子：
4.8
通讯作者：
Nizet, Victor
中科院分区：
文献类型：
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作者：
Anderson, Ericka L.;Cole, Jason N.;Nizet, Victor
背景：A群链球菌（GAS） M1蛋白结合纤维蛋白原（Fg）阻断吞噬作用并形成促炎复合物。结果：M1和Fg限制了体外咽部角质形成细胞对GAS的粘附和侵袭。结论：SpeB蛋白酶在感染过程中对M1表达和GAS宿主细胞相互作用有不同的调节作用。意义：M1蛋白在体内可阻碍咽部定植。A群链球菌（GAS）是一种主要的人类病原体，可引起多种感染，从单纯的咽炎（链球菌性咽喉炎）到侵袭性疾病，包括坏死性筋膜炎和中毒性休克综合征。表面锚定的GAS M1蛋白是一种经典的毒力因子，通过结合宿主纤维蛋白原（Fg）形成超分子网络，促进吞噬细胞抵抗和夸大炎症。在这项研究中，我们使用了一株毒力强的WT M1T1 GAS菌株及其等基因m1缺陷突变体来检测M1-Fg结合在GAS感染的近端步骤中的作用-与咽上皮的相互作用。M1蛋白的表达使GAS对人咽部角质形成细胞的粘附减少了2倍，在Fg的存在下，这种差异增加到4倍。在固定期，GAS半胱氨酸蛋白酶SpeB对表面M1蛋白的切割消除了Fg的结合，减轻了其对GAS咽细胞粘附的抑制作用。在小鼠鼻腔相关淋巴组织的GAS定植模型中，在等基因菌株竞争试验中，M1蛋白的表达与GAS回收率平均降低6倍相关。因此，GAS M1蛋白- fg结合以一种被SpeB平衡的方式减少了GAS咽细胞的粘附和定植。在向侵袭性GAS疾病转变的过程中，SpeB的失活允许M1-Fg结合，增加病原体吞噬细胞的抵抗力和促炎活性。
Background: The group A Streptococcus (GAS) M1 protein binds fibrinogen (Fg) to block phagocytosis and to form a proinflammatory complex. Results: M1 and Fg limit GAS adherence and invasion of pharyngeal keratinocytes in vitro. Conclusion: Protease SpeB modulates M1 expression and GAS host cell interactions differentially during the course of infection. Significance: M1 protein is shown to impede pharyngeal colonization in vivo.Group A Streptococcus (GAS) is a leading human pathogen producing a diverse array of infections from simple pharyngitis (strep throat) to invasive conditions, including necrotizing fasciitis and toxic shock syndrome. The surface-anchored GAS M1 protein is a classical virulence factor that promotes phagocyte resistance and exaggerated inflammation by binding host fibrinogen (Fg) to form supramolecular networks. In this study, we used a virulent WT M1T1 GAS strain and its isogenic M1-deficient mutant to examine the role of M1-Fg binding in a proximal step in GAS infection-interaction with the pharyngeal epithelium. Expression of the M1 protein reduced GAS adherence to human pharyngeal keratinocytes by 2-fold, and this difference was increased to 4-fold in the presence of Fg. In stationary phase, surface M1 protein cleavage by the GAS cysteine protease SpeB eliminated Fg binding and relieved its inhibitory effect on GAS pharyngeal cell adherence. In a mouse model of GAS colonization of nasal-associated lymphoid tissue, M1 protein expression was associated with an average 6-fold decreased GAS recovery in isogenic strain competition assays. Thus, GAS M1 protein-Fg binding reduces GAS pharyngeal cell adherence and colonization in a fashion that is counterbalanced by SpeB. Inactivation of SpeB during the shift to invasive GAS disease allows M1-Fg binding, increasing pathogen phagocyte resistance and proinflammatory activities.