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 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.
Highlights
Streptococcus pyogenes is an important human pathogen that may cause a number of conditions from harmless throat infections to invasive diseases such as septicemia, necrotizing soft-tissue infections (NSTI), and streptococcal toxic shock syndrome [1]
Natural infections with S. pyogenes only occur in humans, and in the present work we investigate the immunomodulatory properties of streptococcal inhibitor of complement (SIC) in human blood
The results show that SIC is secreted from the wild-type, but not expressed in the SICmutant strain, and they reveal that SIC is the most abundant protein secreted from S. pyogenes under these culture conditions (Figure 1A)
Summary
Streptococcus pyogenes (group A streptococcus, GAS) is an important human pathogen that may cause a number of conditions from harmless throat infections to invasive diseases such as septicemia, necrotizing soft-tissue infections (NSTI), and streptococcal toxic shock syndrome [1]. The innate immune system is the first response to S. pyogenes infections To counteract this and Abbreviations: GAS, group A streptococci; NSTI, necrotizing soft-tissue infection; AMPs, antimicrobial peptides; protein SIC, streptococcal inhibitor of complement; histones, calf thymus histones; SN, supernatant; CFUs, colony-forming units; HMGB1, high-mobility group box 1; HBP, heparin-binding protein; PBS-T, PBS containing 0.05% (v/v) Tween-20; PBS-G, PBS containing 5 mM glucose; ACIA, acquired computerized image analysis; TH, Todd–Hewitt; mga, multiple gene regulator of GAS. SIC/Histone Complexes Boost Inflammation maintain colonization, S. pyogenes is equipped with an arsenal of virulence factors (for an excellent review, see Ref [2]). One of these is protein SIC (Streptococcal Inhibitor of Complement). Apart from SIC, mga induces transcription of genes coding for proteins involved in adherence, internalization, and immune evasion [11]
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