Streptococcus 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.
Bibliographical noteFunding Information:
We thank Berit Olofsson for excellent technical assistance with isolation of CD14+ monocytes. We thank Dr. Oonagh Shannon and Frida Palm for access to and excellent technical assistant with the flow cytometer. We thank Tilde Andersson and Dr. Gizem Ert?rk-Bergdahl for excellent technical assistance with the Biacore/SPR experiments. This study was funded by grants from Knut and Alice Wallenberg Foundation, Alfred ?sterlund Foundation, Hansa Biopharma, the Swedish Government Funds for Clinical Research (ALF), Royal Physiographic Society of Lund and the Swedish Research Council (project 7480). Conceptualization: A.N. I.-M.F. and L.B. Methodology: A.N. and W.B. Validation: A.N. I.-M.F. and L.B. Formal analysis: A.N. L.H. and C.K. Investigation: A.N. L.H. C.K. and I.-M.F. Data curation: L.H. and C.K. Writing ? Original draft: A.N. I.-M.F. and L.B. Writing ? Review & Editing: A.N. L.H. C.K. W.B. I.-M.F. and L.B. Visualization: A.N. Supervision: A.N. and L.B. Project administration: A.N. and L.B. Funding acquisition: A.N. I.-M.F. and L.B. The authors declare no competing interest.
© 2021 The Authors
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Subject classification (UKÄ)
- Infectious Medicine
- Microbiology in the medical area
- Clinical Microbiology