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.
Highlights
Streptococcus pyogenes, known as Group A streptococcus (GAS), is a Gram-positive human pathogen causing an exceptionally broad range of infectious diseases [1]
Streptococcus pyogenes is an important human pathogen that causes a broad range of diseases
We further show that IFNbeta, 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
Summary
Streptococcus pyogenes, known as Group A streptococcus (GAS), is a Gram-positive human pathogen causing an exceptionally broad range of infectious diseases [1]. Systemic infections with S. pyogenes can develop into life-threatening diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome that occur in ,10000 cases in the US annually resulting in ,1500 deaths [2]. The wide spectrum of S. pyogenes-related diseases arises from diversity in the genetic inventory of both the host and the pathogen [3,4,5,6]. Genetic linkage analysis of mouse strains differing in their susceptibility to S. pyogenes infections demonstrated importance of the innate immune system [7]. Animal studies confirmed an essential role of macrophages and dendritic cells (DCs) in protection against S. pyogenes infections [8,9]
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