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

被引:110
作者
Gratz, Nina [1 ]
Hartweger, Harald [1 ]
Matt, Ulrich [2 ,3 ]
Kratochvill, Franz [1 ]
Janos, Marton [1 ]
Sigel, Stefanie [2 ,3 ]
Drobits, Barbara [4 ]
Li, Xiao-Dong [5 ]
Knapp, Sylvia [2 ,3 ]
Kovarik, Pavel [1 ]
机构
[1] Univ Vienna, Dept Microbiol Immunobiol & Genet, Max F Perutz Labs, Vienna, Austria
[2] Med Univ Vienna, Austrian Acad Sci, Res Ctr Mol Med, CEMM, Vienna, Austria
[3] Med Univ Vienna, Dept Internal Med 1, Div Infect Dis & Trop Med, Vienna, Austria
[4] Med Univ Vienna, Dept Internal Med 1, Inst Canc Res, Vienna, Austria
[5] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA
基金
奥地利科学基金会;
关键词
GROUP-A STREPTOCOCCI; CYTOSOLIC DNA; MOLECULAR-BASIS; INNATE; RECOGNITION; INDUCTION; PHAGOCYTOSIS; MACROPHAGES; ACTIVATION; RESISTANCE;
D O I
10.1371/journal.ppat.1001345
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
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.
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页数:16
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