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Published on: December 9, 2022
The ScpC protease of Streptococcus pyogenes affects the outcome of sepsis in a murine model
Hong Sjölinder1, Lena Lövkvist, Laura Plant
1Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, Uppsala, Sweden.
Abstract:
The ScpC protease of Streptococcus pyogenes degrades interleukin-8 (IL-8), a chemokine that mediates neutrophil transmigration and activation. The ability to degrade IL-8 differs dramatically among clinical isolates of S. pyogenes. Bacteria expressing ScpC overcome immune clearance by preventing the recruitment of neutrophils in soft tissue infection of mice. To study the role of ScpC in streptococcal sepsis, we generated an ScpC mutant that did not degrade IL-8 and thus failed to prevent the recruitment of immune cells as well as to cause disease after soft tissue infection. In a murine model of sepsis, challenge with the ScpC mutant resulted in more severe systemic disease with higher bacteremia levels and mortality than did challenge with the wild-type strain. As expected, the blood level of KC, the murine IL-8 homologue, increased in mice infected with the ScpC mutant. However, the elevated KC levels did not influence neutrophil numbers in blood, as it did in soft tissue, indicating that additional factors contributed to neutrophil transmigration in blood. In addition, the absence of ScpC increased tumor necrosis factor, IL-6, and C5a levels in blood, which contributed to disease severity. Thus, the ScpC mutant triggers high neutrophil infiltration but not lethal outcome after soft tissue infection, whereas intravenous infection leads to highly aggressive systemic disease.
Insights
Streptococcus pyogenes ScpC protease degrades interleukin-8 (IL-8), hindering neutrophil recruitment. A mutant lacking ScpC caused severe sepsis, demonstrating ScpC
Area of Science:
- Microbiology
- Immunology
- Pathogenesis
Background:
- Streptococcus pyogenes possesses a protease, ScpC, that degrades interleukin-8 (IL-8).
- IL-8 is crucial for neutrophil recruitment and activation in inflammatory responses.
- Degradation of IL-8 by ScpC impacts bacterial evasion of the host immune system.
Purpose of the Study:
- To investigate the role of ScpC in Streptococcus pyogenes pathogenesis, particularly in sepsis.
- To determine the impact of IL-8 degradation by ScpC on immune cell recruitment and disease severity.
Main Methods:
- Generation of an ScpC mutant of Streptococcus pyogenes unable to degrade IL-8.
- Infection of a murine model with wild-type and ScpC mutant strains.
- Analysis of bacterial load, immune cell infiltration (neutrophils), and cytokine levels (KC, TNF-α, IL-6, C5a) in blood and tissues.
Main Results:
- The ScpC mutant failed to prevent neutrophil recruitment in soft tissue infections.
- In a murine sepsis model, the ScpC mutant caused increased bacteremia, mortality, and elevated KC, TNF-α, IL-6, and C5a levels compared to the wild-type.
- While KC levels rose in sepsis, neutrophil numbers in blood were not solely influenced by KC, suggesting other factors contribute to transmigration.
Conclusions:
- ScpC plays a significant role in modulating the host immune response during Streptococcus pyogenes infection.
- The absence of ScpC leads to more aggressive systemic disease and higher mortality in a murine sepsis model.
- ScpC's IL-8 degrading activity is critical for immune evasion and virulence in soft tissue infections, while its absence exacerbates systemic disease.
