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Protein SIC secreted from Streptococcus pyogenes forms complexes with extracellular histones that boost cytokine production

Westman, Johannes LU ; Chakrakodi, Bhavya; Snäll, Johanna; Mörgelin, Matthias LU ; Madsen, Martin Bruun; Hyldegaard, Ole; Neumann, Ariane LU ; Frick, Inga Maria LU ; Norrby-Teglund, Anna and Björck, Lars LU , et al. (2018) In Frontiers in Immunology 9(FEB). p.1-14
Abstract

Innate immunity relies on an effective recognition of the pathogenic microorganism as well as on endogenous danger signals. While bacteria in concert with their secreted virulence factors can cause a number of inflammatory reactions, danger signals released at the site of infection may in addition determine the amplitude of such responses and influence the outcome of the disease. Here, we report that protein SIC, Streptococcal Inhibitor of Complement, an abundant secreted protein from Streptococcus pyogenes, binds to extracellular histones, a group of danger signals released during necrotizing tissue damage. This interaction leads to the formation of large aggregates in vitro. Extracellular histones and SIC are abundantly expressed and... (More)

Innate immunity relies on an effective recognition of the pathogenic microorganism as well as on endogenous danger signals. While bacteria in concert with their secreted virulence factors can cause a number of inflammatory reactions, danger signals released at the site of infection may in addition determine the amplitude of such responses and influence the outcome of the disease. Here, we report that protein SIC, Streptococcal Inhibitor of Complement, an abundant secreted protein from Streptococcus pyogenes, binds to extracellular histones, a group of danger signals released during necrotizing tissue damage. This interaction leads to the formation of large aggregates in vitro. Extracellular histones and SIC are abundantly expressed and seen colocalized in biopsies from patients with necrotizing soft-tissue infections caused by S. pyogenes. In addition, binding of SIC to histones neutralized their antimicrobial activity. Likewise, the ability of histones to induce hemolysis was inhibited in the presence of SIC. However, when added to whole blood, SIC was not able to block the pro-inflammatory effect of histones. Instead SIC boosted the histone-triggered release of a broad range of cytokines and chemokines, including IL-6, TNF-α, IL-8, IL-1β, IL-1ra, G-CSF, and IFN-γ. These results demonstrate that the interaction between SIC and histones has multiple effects on the host response to S. pyogenes infection.

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keywords
Antimicrobial peptide, Cytokines, Extracellular histones, Innate immunity, Streptococcal inhibitor of complement, Streptococcus pyogenes, Toll-like receptor
in
Frontiers in Immunology
volume
9
issue
FEB
pages
1 - 14
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85042386051
DOI
10.3389/fimmu.2018.00236
language
English
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yes
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171ce825-21ad-41b6-8074-3c9510e7d7fe
date added to LUP
2018-03-12 09:33:23
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2018-05-29 11:01:05
@article{171ce825-21ad-41b6-8074-3c9510e7d7fe,
  abstract     = {<p>Innate immunity relies on an effective recognition of the pathogenic microorganism as well as on endogenous danger signals. While bacteria in concert with their secreted virulence factors can cause a number of inflammatory reactions, danger signals released at the site of infection may in addition determine the amplitude of such responses and influence the outcome of the disease. Here, we report that protein SIC, Streptococcal Inhibitor of Complement, an abundant secreted protein from Streptococcus pyogenes, binds to extracellular histones, a group of danger signals released during necrotizing tissue damage. This interaction leads to the formation of large aggregates in vitro. Extracellular histones and SIC are abundantly expressed and seen colocalized in biopsies from patients with necrotizing soft-tissue infections caused by S. pyogenes. In addition, binding of SIC to histones neutralized their antimicrobial activity. Likewise, the ability of histones to induce hemolysis was inhibited in the presence of SIC. However, when added to whole blood, SIC was not able to block the pro-inflammatory effect of histones. Instead SIC boosted the histone-triggered release of a broad range of cytokines and chemokines, including IL-6, TNF-α, IL-8, IL-1β, IL-1ra, G-CSF, and IFN-γ. These results demonstrate that the interaction between SIC and histones has multiple effects on the host response to S. pyogenes infection.</p>},
  articleno    = {236},
  author       = {Westman, Johannes and Chakrakodi, Bhavya and Snäll, Johanna and Mörgelin, Matthias and Madsen, Martin Bruun and Hyldegaard, Ole and Neumann, Ariane and Frick, Inga Maria and Norrby-Teglund, Anna and Björck, Lars and Herwald, Heiko},
  keyword      = {Antimicrobial peptide,Cytokines,Extracellular histones,Innate immunity,Streptococcal inhibitor of complement,Streptococcus pyogenes,Toll-like receptor},
  language     = {eng},
  month        = {02},
  number       = {FEB},
  pages        = {1--14},
  publisher    = {Frontiers Media S. A.},
  series       = {Frontiers in Immunology},
  title        = {Protein SIC secreted from Streptococcus pyogenes forms complexes with extracellular histones that boost cytokine production},
  url          = {http://dx.doi.org/10.3389/fimmu.2018.00236},
  volume       = {9},
  year         = {2018},
}