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.
| Original language | English (US) |
|---|---|
| Article number | e1001345 |
| Journal | PLoS Pathogens |
| Volume | 7 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2011 |
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ASJC Scopus subject areas
- Microbiology
- Parasitology
- Virology
- Immunology
- Genetics
- Molecular Biology
Cite this
Type I Interferon Production Induced By Streptococcus Pyogenes-Derived Nucleic Acids is Required for Host Protection. / Gratz, Nina; Hartweger, Harald; Matt, Ulrich; Kratochvill, Franz; Janos, Marton; Sigel, Stefanie; Drobits, Barbara; Li, Xiao Dong; Knapp, Sylvia; Kovarik, Pavel.
In: PLoS Pathogens, Vol. 7, No. 5, e1001345, 05.2011.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Type I Interferon Production Induced By Streptococcus Pyogenes-Derived Nucleic Acids is Required for Host Protection
AU - Gratz, Nina
AU - Hartweger, Harald
AU - Matt, Ulrich
AU - Kratochvill, Franz
AU - Janos, Marton
AU - Sigel, Stefanie
AU - Drobits, Barbara
AU - Li, Xiao Dong
AU - Knapp, Sylvia
AU - Kovarik, Pavel
PY - 2011/5
Y1 - 2011/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79958055165&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79958055165&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1001345
DO - 10.1371/journal.ppat.1001345
M3 - Article
C2 - 21625574
AN - SCOPUS:79958055165
VL - 7
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 5
M1 - e1001345
ER -