TLR-Independent Type I Interferon Induction in Response to an Extracellular Bacterial Pathogen via Intracellular Recognition of Its DNA

Abstract

SUMMARY 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-β 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-β 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-α/-β 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.

RNA and β-Hemolysin of Group B Streptococcus Induce Interleukin-1β (IL-1β) by Activating NLRP3 Inflammasomes in Mouse Macrophages

“…Previously, we showed that GBS induces IFN-␤ production in a Toll-like receptor-independent fashion in macrophages by an unknown DNA sensor (12). We also showed that GBS induces IL-1␤ production in an NLRP3-dependent manner in dendritic cells (13).…”

“…agalactiae strains NEM 316 (type III) were obtained from the blood of a neonate with sepsis as described (12). Strains NEM ⌬cylE and NEM ⌬cfb were NEM 316-derived mutants that lack CylE, a putative n-acetyltransferase in ornithine rhamnolipid biosynthesis, or CfB, which encodes the co-hemolysin (CAMP (Christie Atkins Munch-Petersen) factor), (12).…”

“…agalactiae strains NEM 316 (type III) were obtained from the blood of a neonate with sepsis as described (12). Strains NEM ⌬cylE and NEM ⌬cfb were NEM 316-derived mutants that lack CylE, a putative n-acetyltransferase in ornithine rhamnolipid biosynthesis, or CfB, which encodes the co-hemolysin (CAMP (Christie Atkins Munch-Petersen) factor), (12). Two hyperhemolytic strains were produced: NEM 2802 by deleting * This work was supported, in whole or in part, by National Institutes of Health Grant RO1 AI52455 (to D. T. G., P. H., and P. T.-C.) and U24 AI082663 (to D. T. G., N. S., E. L., and S. G.) and by the German Research Council (DFG HE 3127/5-1 to P. H.).…”

Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response

“…However, the system responsible for double-stranded DNA (dsDNA)-induced innate immune responses, although extensively analyzed, is still unclear. Microbial dsDNA derived from bacteria and DNA viruses, as well as synthetic dsDNA, induce both type I IFN (IFN) production and other proinf lammatory cytokines, such as interleukin IL-1␤ and IL-6 (1)(2)(3)(4)(5)(6)(7)(8)(9). It is also known that undigested host genomic DNA accumulated in phagocytes can also induce aberrant activation of the immune response (10,11).…”

Phagosomal signaling byBorrelia burgdorferiin human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-β

“…Although production of type I IFNs was previously ascribed solely to antiviral immune responses (10), it now is well established that both intracellular (11)(12)(13)(14) and extracellular bacteria (11,(15)(16)(17) also induce transcription of these cytokines. Bacteria can elicit type I IFNs either by activating TLRs (11,12) or through TLR-independent recognition of bacterial pathogenassociated molecular patterns (PAMPs) within the host cell cytosol (11,18).…”