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.

Bacterial RNA: An Underestimated Stimulus for Innate Immune Responses

“…Mancuso et al (30) reported that purified RNA derived from Streptococcus agalactiae (group B Streptococcus [GBS]) induced IFN-b in mouse mDCs in a TLR7-dependent manner. In contrast, Gratz et al (33) proposed that DOTAP-packaged lysates from Streptococcus pyogenes induced IFN-b by an RNA-dependent, but TLR7-independent, mechanism. Similarly, production of the classical NF-kB-dependent cytokines TNF and IL-1b upon bacterial RNA stimulation did not require TLR7-mediated signaling in murine BMDMs and mDCs (27,36), although these cells can be efficiently activated by TLR7 small molecule agonists, including imiquimod and R848.…”

“…Further analysis based on the transfection of RNase-or DNasetreated extracts of sonicated S. pyogenes demonstrated that bacterial RNA was critical for mounting IFN-b responses in murine mDCs, yet they were independent of TLR7. In contrast, S. pyogenes DNA was identified as an inducer of type I IFN in BMDMs (33). Together, these data raised the possibility that sensing of microbial RNA might be important for innate immune responses against S. pyogenes.…”

“…Similarly, both human PBMCs and murine bone marrow-derived macrophages (BMDMs) responded to intracellular delivery of total bacterial RNA with TNF production (27)(28)(29)(30). In addition to inducing classical NF-kB-dependent cytokines, bacterial RNA has been identified as a strong trigger of IFN-a in plasmacytoid dendritic cells (pDCs) and of IFN-b in myeloid dendritic cells (mDCs) in an IRF-dependent manner (28,(30)(31)(32)(33)(34). Depending on the model system, the involvement of IRF1, IRF3, IRF5, or IRF7 has been implicated (30,31,33,35).…”

Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells

“…A further study using pDCs from IRF5-deficient mice, carrying or not carrying the DOCK2 mutation, confirmed that IRF5 had little effect on TLR9-stimulated IFNα secretion, but indicated an important role for IRF5 in the secretion of IFNβ (4). IRF5 was also required for the TLR9-stimulated production of IFNβ in the human pDC line CAL-1 (5) and for the production of IFNβ induced by streptococcal RNA in cDCs (6) and by the fungal pathogen Candida albicans in a pathway dependent on the Dectin 1 and Dectin 2 receptors (7). IRF5 was also found to be needed for the production of IFNβ by a small subset of viruses (8,9).…”

Early Inhibition of IL-1β Expression by IFN-γ Is Mediated by Impaired Binding of NF-κB to the IL-1β Promoter but Is Independent of Nitric Oxide

“…Although the critical roles for bacterial DNA and viral RNA in the induction of innate immune responses have been acknowledged for long time, the importance of bRNA recognition has only recently started to be unraveled. It was demonstrated that intracellular delivery of bRNA induced secretion of type I IFNs, as well as proinflammatory cytokines, including TNF, IL-12p40, or IL-1b (10,(14)(15)(16)(17). In plasmacytoid DCs, bRNA-induced production of type I IFNs is mediated by TLR7 (15), whereas the murine receptor TLR13 was identified only recently to sense bRNA in both bone marrow-derived macrophages (BMDMs) and DCs by recognizing a unique nucleotide motif present in the bacterial 23S rRNA (18,19).…”