The Group A Streptococcus Interleukin-8 Protease SpyCEP Promotes Bacterial Intracellular Survival by Evasion of Autophagy

作     者：RenéBergmann Giuseppe Gulotta Federica Andreoni Tomoko Sumitomo Shigetada Kawabata Annelies S.Zinkernagel Gursharan S.Chhatwal Victor Nizet Manfred Rohde Satoshi Uchiyama René Bergmann;Giuseppe Gulotta;Federica Andreoni;Tomoko Sumitomo;Shigetada Kawabata;Annelies S.Zinkernagel;Gursharan S.Chhatwal;Victor Nizet;Manfred Rohde;Satoshi Uchiyama

作者机构：Central Unit for Microscopy(ZEIM)Helmholtz Centre for Infection ResearchBraunschweigGermany Division of Infectious Diseases and Hospital EpidemiologyUniversity Hospital ZurichZurichSwitzerland Department of Oral and Molecular MicrobiologyOsaka University Graduate School of DentistrySuita-OsakaJapan Division of Host-Microbe Systems and TherapeuticsDepartment of PediatricsUniversity of CaliforniaSan DiegoLa JollaCalifornia 

出 版 物：《Infectious Microbes & Diseases》 (感染微生物与疾病（英文）)

年 卷 期：2022年第4卷第3期

页      面：116-123页

学科分类：0710[理学-生物学] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1001[医学-基础医学(可授医学、理学学位)] 100102[医学-免疫学] 10[医学] 

基　　金：supported in part by Marie Skłodowska-Curie actions Intra-European Fellowships(MC-IEF-329520) The Naito Foundation,The Takeda Science Foundation,and the US National Institutes of Health(R01-AI145325)。 

主　　题：group A Streptococcus SpyCEP virulence factor epithelial cells intracellular survival autophagy xenophagy calpain 

摘      要：Autophagy serves an innate immune function in defending the host against invading bacteria,including group A Streptococcus(GAS).Autophagy is regulated by numerous host proteins,including the endogenous negative regulator calpain,a cytosolic protease.Globally disseminated serotypeM1T1 GAS strains associated with high invasive disease potential express numerous virulence factors and resist autophagic clearance.Upon in vitro infection of human epithelial cell lines with representative wild-type GAS M1T1 strain 5448(M1.5448),we observed increased calpain activation linked to a specific GAS virulence factor,the interleukin-8 protease SpyCEP.Calpain activation inhibited autophagy and decreased capture of cytosolic GAS in autophagosomes.In contrast,the serotype M6 GAS strain JRS4(M6.JRS4),which is highly susceptible to host autophagy-mediated killing,expresses low levels of SpyCEP and does not activate calpain.Overexpression of SpyCEP in M6.JRS4 stimulated calpain activation,inhibited autophagy,and significantly decreased bacterial capture in autophagosomes.These paired loss-and gain-of-function studies reveal a novel role for the bacterial protease SpyCEP in enabling GAS M1 evasion of autophagy and host innate immune clearance.