Type I Interferon Production Induced by Streptococcus pyogenes-Derived Nucleic Acids Is Required for Host Protection

Abstract

Streptococcus pyogenes is a Gram-positive human pathogen that is recognized by yet unknown pattern recognition receptors (PRRs). Engagement of these receptor molecules during infection with S. pyogenes, a largely extracellular bacterium with limited capacity for intracellular survival, causes innate immune cells to produce inflammatory mediators such as TNF, but also type I interferon (IFN). Here we show that signaling elicited by type I IFNs is required for successful defense of mice against lethal subcutaneous cellulitis caused by S. pyogenes. Type I IFN signaling was accompanied with reduced neutrophil recruitment to the site of infection. Mechanistic analysis revealed that macrophages and conventional dendritic cells (cDCs) employ different signaling pathways leading to IFN-beta production. Macrophages required IRF3, STING, TBK1 and partially MyD88, whereas in cDCs the IFN-beta production was fully dependent on IRF5 and MyD88. Furthermore, IFN-beta production by macrophages was dependent on the endosomal delivery of streptococcal DNA, while in cDCs streptococcal RNA was identified as the IFN-beta inducer. Despite a role of MyD88 in both cell types, the known IFN-inducing TLRs were individually not required for generation of the IFN-beta response. These results demonstrate that the innate immune system employs several strategies to efficiently recognize S. pyogenes, a pathogenic bacterium that succeeded in avoiding recognition by the standard arsenal of TLRs.

Author Summary

Streptococcus pyogenes is an important human pathogen that causes a broad range of diseases. The bacterium colonizes the throat and the skin where it can evoke usually mild illness such as strep throat or scarlet fever. Systemic infections with S. pyogenes are less frequent but can develop into life-threatening diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. The immune system launches a usually successful response that is initiated by a so far not understood recognition of this pathogen by the cells of the innate immune system. These cells produce upon infection a variety of cytokines that orchestrate a full blown protective response. Among these cytokines, type I interferons play a critical role as demonstrated by our study. We further show that IFN-beta, the key type I interferon, is produced only after macrophages and dendritic cells have taken up the pathogen and liberated the bacterial nucleic acids for recognition in the intracellular vesicles. Importantly, macrophages and dendritic cells recognize different nucleic acids and employ different signaling pathways to respond. Our data suggest that the innate immune system employs several strategies to efficiently recognize S. pyogenes, a pathogenic bacterium that succeeded in avoiding recognition by the standard recognition mechanisms.