Introduction:
Streptococcus pyogenes (group A Streptococcus) commonly causes pharyngitis in humans, with severe invasive diseases and immune sequelae being an infrequent consequence. The ability of S. pyogenes to invade the host and establish an infection likely involves subversion of host immune defences, however the innate immune responses and signalling pathways that respond to S. pyogenes are not well understood.
Methods:
In this study, we used RNAseq and ELISAs to characterise the inflammatory responses of primary human tonsil epithelial cells to infection with a laboratory-adapted M6 strain (JRS4) and a clinical isolate of the globally disseminated M1T1 clone (5448), the leading cause of pharyngitis and severe invasive S. pyogenes infections globally.
Results:
Both strains induced the expression of genes encoding a wide range of inflammatory mediators, including IL-8. Pathway analysis revealed differentially expressed genes were enriched in transcription factor networks which regulate IL-8 expression, such as AP-1 and NFAT. Surprisingly, while M6 infection induced strong secretion of IL-6 and IL-8, M1T1 infection did not induce IL-6 secretion, and suppressed IL-8 levels below mock-treated cells. This suggests that M1T1 post-transcriptionally downregulates host IL-8 production. IL-8 secretion was restored by infection with M1T1∆cepA, a knockout mutant for the cysteine protease SPYcep, which degrades human IL-8 and related chemokines.
Conclusion:
Our results thus suggest that the pathogenic M1T1 clone induces a strong pro-inflammatory response in the human tonsil epithelium, but overcomes this host response by selectively degrading host-protective neutrophil-recruiting chemokines to benefit infection.