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Streptococcal M protein promotes IL-10 production by cGAS-independent activation of the STING signaling pathway

Movert, Elin LU ; Lienard, Julia LU ; Valfridsson, Christine LU ; Nordström, Therése LU ; Johansson-Lindbom, Bengt LU and Carlsson, Fredric LU (2018) In PLoS Pathogens 14(3).
Abstract

From an evolutionary point of view a pathogen might benefit from regulating the inflammatory response, both in order to facilitate establishment of colonization and to avoid life-threatening host manifestations, such as septic shock. In agreement with this notion Streptococcus pyogenes exploits type I IFN-signaling to limit detrimental inflammation in infected mice, but the host-pathogen interactions and mechanisms responsible for induction of the type I IFN response have remained unknown. Here we used a macrophage infection model and report that S. pyogenes induces anti-inflammatory IL-10 in an M protein-dependent manner, a function that was mapped to the B- and C-repeat regions of the M5 protein. Intriguingly, IL-10 was produced... (More)

From an evolutionary point of view a pathogen might benefit from regulating the inflammatory response, both in order to facilitate establishment of colonization and to avoid life-threatening host manifestations, such as septic shock. In agreement with this notion Streptococcus pyogenes exploits type I IFN-signaling to limit detrimental inflammation in infected mice, but the host-pathogen interactions and mechanisms responsible for induction of the type I IFN response have remained unknown. Here we used a macrophage infection model and report that S. pyogenes induces anti-inflammatory IL-10 in an M protein-dependent manner, a function that was mapped to the B- and C-repeat regions of the M5 protein. Intriguingly, IL-10 was produced downstream of type I IFN-signaling, and production of type I IFN occurred via M protein-dependent activation of the STING signaling pathway. Activation of STING was independent of the cytosolic double stranded DNA sensor cGAS, and infection did not induce detectable release into the cytosol of either mitochondrial, nuclear or bacterial DNA–indicating DNA-independent activation of the STING pathway in S. pyogenes infected macrophages. These findings provide mechanistic insight concerning how S. pyogenes induces the type I IFN response and identify a previously unrecognized macrophage-modulating role for the streptococcal M protein that may contribute to curb the inflammatory response to infection.

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Contribution to journal
publication status
published
subject
in
PLoS Pathogens
volume
14
issue
3
publisher
Public Library of Science
external identifiers
  • scopus:85044824499
ISSN
1553-7366
DOI
10.1371/journal.ppat.1006969
language
English
LU publication?
yes
id
593c9db9-97ad-4125-ab7e-46f2ef4149a0
date added to LUP
2018-04-13 15:19:30
date last changed
2018-07-14 03:00:15
@article{593c9db9-97ad-4125-ab7e-46f2ef4149a0,
  abstract     = {<p>From an evolutionary point of view a pathogen might benefit from regulating the inflammatory response, both in order to facilitate establishment of colonization and to avoid life-threatening host manifestations, such as septic shock. In agreement with this notion Streptococcus pyogenes exploits type I IFN-signaling to limit detrimental inflammation in infected mice, but the host-pathogen interactions and mechanisms responsible for induction of the type I IFN response have remained unknown. Here we used a macrophage infection model and report that S. pyogenes induces anti-inflammatory IL-10 in an M protein-dependent manner, a function that was mapped to the B- and C-repeat regions of the M5 protein. Intriguingly, IL-10 was produced downstream of type I IFN-signaling, and production of type I IFN occurred via M protein-dependent activation of the STING signaling pathway. Activation of STING was independent of the cytosolic double stranded DNA sensor cGAS, and infection did not induce detectable release into the cytosol of either mitochondrial, nuclear or bacterial DNA–indicating DNA-independent activation of the STING pathway in S. pyogenes infected macrophages. These findings provide mechanistic insight concerning how S. pyogenes induces the type I IFN response and identify a previously unrecognized macrophage-modulating role for the streptococcal M protein that may contribute to curb the inflammatory response to infection.</p>},
  articleno    = {e1006969},
  author       = {Movert, Elin and Lienard, Julia and Valfridsson, Christine and Nordström, Therése and Johansson-Lindbom, Bengt and Carlsson, Fredric},
  issn         = {1553-7366},
  language     = {eng},
  month        = {03},
  number       = {3},
  publisher    = {Public Library of Science},
  series       = {PLoS Pathogens},
  title        = {Streptococcal M protein promotes IL-10 production by cGAS-independent activation of the STING signaling pathway},
  url          = {http://dx.doi.org/10.1371/journal.ppat.1006969},
  volume       = {14},
  year         = {2018},
}