Header

UZH-Logo

Maintenance Infos

The group A Streptococcus interleukin-8 protease SpyCEP promotes bacterial intracellular survival by evasion of autophagy


Bergmann, René; Gulotta, Giuseppe; Andreoni, Federica; Sumitomo, Tomoko; Kawabata, Shigetada; Zinkernagel, Annelies S; Chhatwal, Gursharan S; Nizet, Victor; Rohde, Manfred; Uchiyama, Satoshi (2022). The group A Streptococcus interleukin-8 protease SpyCEP promotes bacterial intracellular survival by evasion of autophagy. Infectious Microbes & Diseases, 4(3):116-123.

Abstract

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.

Abstract

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.

Statistics

Citations

Dimensions.ai Metrics

Altmetrics

Downloads

6 downloads since deposited on 06 Nov 2023
6 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, not_refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Epidemiology
Health Sciences > Microbiology (medical)
Health Sciences > Infectious Diseases
Uncontrolled Keywords:Group A Streptococcus; SpyCEP; autophagy; calpain; epithelial cells; intracellular survival; virulence factor; xenophagy
Language:English
Date:September 2022
Deposited On:06 Nov 2023 15:34
Last Modified:27 Jun 2024 03:36
Publisher:Lippincott Williams & Wilkins
ISSN:2641-5917
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1097/im9.0000000000000098
PubMed ID:37333426
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-ShareAlike 4.0 International (CC BY-SA 4.0)