Open AccessThe Group A Streptococcus Interleukin-8 Protease SpyCEP Promotes Bacterial Intracellular Survival by Evasion of Autophagy
Author(s) -
René Bergmann,
Giuseppe Gulotta,
Federica Andreoni,
Tomoko Sumitomo,
Shigetada Kawabata,
Annelies S. Zinkernagel,
Gursharan S. Chhatwal,
Victor Nizet,
Manfred Rohde,
Satoshi Uchiyama
Publication year - 2022
Publication title -
infectious microbes and diseases
Language(s) - English
Resource type - Journals
eISSN - 2096-7241
pISSN - 2641-5917
DOI - 10.1097/im9.0000000000000098
Subject(s) - calpain , autophagy , virulence factor , microbiology and biotechnology , protease , biology , virulence , innate immune system , immune system , apoptosis , immunology , biochemistry , enzyme , gene
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 serotype M1T1 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 IL-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.