A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues
A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues
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DOI：
10.1038/sj.emboj.7601327
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发表时间：
2006-10-04
期刊：
影响因子：
11.4
通讯作者：
Hanski, Emanuel
中科院分区：
文献类型：
--
作者：
Hidalgo-Grass, Carlos;Mishalian, Inbal;Hanski, Emanuel
A组链球菌（GAS）导致人类的致命感染，称为坏死性筋膜炎（NF）。感染的皮下组织从NF患者和小鼠挑战相同的GAS菌株具有高的细菌负荷，但浸润性多形核白细胞（PMN）的显着缺乏。受损的PMN募集归因于GAS丝氨酸肽酶对趋化因子IL-8的降解。在这里，我们使用生物信息学方法结合靶点突变来鉴定该肽酶为ScpC。我们发现SilCR信息素通过双组分系统SilA/B下调scpC转录。此外，我们证明，在体外，ScpC降解CXC趋化因子：IL-8（人），KC和MIP-2（均为鼠）。此外，使用人类NF的小鼠模型，我们证明，ScpC，而不是C5 a肽酶ScpA，是一个必不可少的毒力因子。ScpC缺陷突变体对未治疗的小鼠是无害的，但对PMN耗尽的小鼠是致命的。ScpC在感染的皮肤组织中局部降解KC和MIP-2，抑制PMN募集。总之，ScpC代表了一种新的GAS毒力因子，其功能是直接抑制宿主先天免疫应答的关键元件。
Group A Streptococcus (GAS) causes the life-threatening infection in humans known as necrotizing fasciitis (NF). Infected subcutaneous tissues from an NF patient and mice challenged with the same GAS strain possessed high bacterial loads but a striking paucity of infiltrating polymorphonuclear leukocytes (PMNs). Impaired PMN recruitment was attributed to degradation of the chemokine IL-8 by a GAS serine peptidase. Here, we use bioinformatics approach coupled with target mutagenesis to identify this peptidase as ScpC. We show that SilCR pheromone downregulates scpC transcription via the two-component system-SilA/B. In addition, we demonstrate that in vitro, ScpC degrades the CXC chemokines: IL-8 (human), KC, and MIP-2 (both murine). Furthermore, using a murine model of human NF, we demonstrate that ScpC, but not the C5a peptidase ScpA, is an essential virulence factor. An ScpC-deficient mutant is innocuous for untreated mice but lethal for PMN-depleted mice. ScpC degrades KC and MIP-2 locally in the infected skin tissues, inhibiting PMN recruitment. In conclusion, ScpC represents a novel GAS virulence factor functioning to directly inactivate a key element of the host innate immune response.