Abstract
SummaryStreptococcus pyogenes is a major bacterial pathogen in the human population and isolates of the clinically important M1 serotype secrete protein Streptococcal inhibitor of complement (SIC) known to interfere with human innate immunity. Here we find that SIC from M1 bacteria interacts with TLR2 and CD14 on monocytes leading to the activation of the NF-κB and p38 MAPK pathways and the release of several pro-inflammatory cytokines (e.g. TNFα and INFγ). In human plasma, SIC binds clusterin and histidine-rich glycoprotein, and whole plasma, and these two purified plasma proteins enhanced the activation of monocytes by SIC. Isolates of the M55 serotype secrete an SIC homolog, but this protein did not activate monocytes. M1 isolates are common in cases of invasive S. pyogenes infections characterized by massive inflammation, and the results of this study indicate that the pro-inflammatory property of SIC contributes to the pathology of these severe clinical conditions.
Highlights
Streptococcus pyogenes is a significant pathogen causing a wide range of infections and post-infection sequelae in the human population (Carapetis et al, 2005)
We find that Streptococcal inhibitor of complement (SIC) from M1 bacteria interacts with TLR2 and CD14 on monocytes leading to the activation of the NF-kB and p38 MAPK pathways and the release of several pro-inflammatory cytokines (e.g. TNFa and INFg)
SIC binds clusterin and histidine-rich glycoprotein, and whole plasma, and these two purified plasma proteins enhanced the activation of monocytes by SIC
Summary
Streptococcus pyogenes is a significant pathogen causing a wide range of infections and post-infection sequelae in the human population (Carapetis et al, 2005). Based on sequence variation in the NH2-terminal surface-exposed tip of M protein, isolates of S. pyogenes are divided into more than 200 M serotypes, and since the 1980s strains of the M1 serotype have dominated worldwide and are frequently isolated from patients with severe invasive infections causing at least 150,000 deaths annually (Carapetis et al, 2005). SIC enhances the ability of M1 bacteria to colonize the mouse mucosal surface after intranasal infection (Lukomski et al, 2000) and blocks the activity of antibacterial proteins and peptides (Fernie-King et al, 2002; Frick et al, 2003; Egesten et al, 2007) In addition, SIC promotes bacterial growth in human blood and virulence in a murine model of systemic infection (Pence et al, 2010). SIC inhibits the antibacterial activity of histones, and complexes between histones and SIC boost histone-triggered release of cytokines and chemokines in human blood (Westman et al, 2018), further underlining the multiple effects of SIC on innate immunity and the host-bacteria relationship
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