TY - JOUR
T1 - Protein SIC secreted from Streptococcus pyogenes forms complexes with extracellular histones that boost cytokine production
AU - Westman, Johannes
AU - Chakrakodi, Bhavya
AU - Snäll, Johanna
AU - Mörgelin, Matthias
AU - Madsen, Martin Bruun
AU - Hyldegaard, Ole
AU - Neumann, Ariane
AU - Frick, Inga Maria
AU - Norrby-Teglund, Anna
AU - Björck, Lars
AU - Herwald, Heiko
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Antimicrobial peptide
KW - Cytokines
KW - Extracellular histones
KW - Innate immunity
KW - Streptococcal inhibitor of complement
KW - Streptococcus pyogenes
KW - Toll-like receptor
U2 - 10.3389/fimmu.2018.00236
DO - 10.3389/fimmu.2018.00236
M3 - Journal article
C2 - 29520265
AN - SCOPUS:85042386051
SN - 1664-3224
VL - 9
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 236
ER -