TLR-independent type I interferon induction in response to an extracellular bacterial pathogen via intracellular recognition of its DNA.
Type I interferon (IFN) is an important host defense cytokine against intracellular pathogens, mainly viruses. In assessing IFN production in response to group B streptococcus (GBS), we find that IFN-beta was produced by macrophages upon stimulation with both heat-killed and live GBS. Exposure of macrophages to heat-killed GBS activated a Toll-like receptor (TLR)-dependent pathway, whereas live GBS activated a TLR/NOD/RIG-like receptor (RLR)-independent pathway. This latter pathway required bacterial phagocytosis, proteolytic bacterial degradation, and phagolysosomal membrane destruction by GBS pore-forming toxins, leading to the release of bacterial DNA into the cytosol. GBS DNA in the cytosol induced IFN-beta production via a pathway dependent on the activation of the serine-threonine kinase TBK1 and phosphorylation of the transcription factor IRF3. Thus, activation of IFN-alpha/-beta production during infection with GBS, commonly considered an extracellular pathogen, appears to result from the interaction of GBS DNA with a putative intracellular DNA sensor or receptor.
Charrel-Dennis
Marie
M
Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Latz
Eicke
E
Halmen
Kristen A
KA
Trieu-Cuot
Patrick
P
Fitzgerald
Katherine A
KA
Kasper
Dennis L
DL
Golenbock
Douglas T
DT
D000818:Animals; D002478:Cells, Cultured; D004269:DNA, Bacterial / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013292:Streptococcus agalactiae / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*
D004269:DNA, Bacterial; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; D051193:Toll-Like Receptors; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases