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

PLoS Pathogens

Stefanie Sigel¹  Ulrich Matt¹  Sylvia Knapp¹  Xiao-Dong Li²  Barbara Drobits³  Nina Gratz⁴  Franz Kratochvill⁴  Harald Hartweger⁴  Pavel Kovarik⁴  Marton Janos⁴ 

[1] CEMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences and Department of Internal Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria;Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas, United States of America;Institute for Cancer Research, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria;Max F. Perutz Laboratories, Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria

关键词: Streptococcus pyogenes;    RNA extraction;    Immune receptor signaling;    Macrophages;    Bacterial pathogens;    Nucleic acids;    Small interfering RNAs;    Enzyme-linked immunoassays;   

DOI  :  10.1371/journal.ppat.1001345

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY