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

PLoS Pathog. 2018 Mar 26;14(3):e1006969. doi: 10.1371/journal.ppat.1006969. eCollection 2018 Mar.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Bacterial / genetics
  • Antigens, Bacterial / metabolism*
  • Bacterial Outer Membrane Proteins / genetics
  • Bacterial Outer Membrane Proteins / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Host-Pathogen Interactions*
  • Immunity, Innate
  • Interferon Type I / metabolism
  • Interleukin-10 / metabolism*
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism*
  • Signal Transduction
  • Streptococcal Infections / genetics
  • Streptococcal Infections / metabolism*
  • Streptococcal Infections / microbiology
  • Streptococcus pyogenes / physiology*


  • Antigens, Bacterial
  • Bacterial Outer Membrane Proteins
  • Carrier Proteins
  • Interferon Type I
  • Membrane Proteins
  • Sting1 protein, mouse
  • streptococcal M protein
  • Interleukin-10
  • Nucleotidyltransferases
  • cGAS protein, mouse

Grants and funding

This study was supported by grants from the Swedish Research Council (Dnr: 2014-3239, FC), as well as the foundations of Emil and Wera Cornell (FC), Crafoord (FC), Gyllenstiernska Krapperup (FC), Alfred Österlund (FC), Clas Groschinsky (FC), Magnus Bergvall (FC), Thelma Zoega (FC), Lars Hierta (FC), Sigurd and Elsa Golje (EM, FC), and the Royal Physiographic Society in Lund (EM, FC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.