TY - JOUR
T1 - Recognition of Borrelia burgdorferi, the lyme disease spirochete, by TLR7 and TLR9 induces a type I IFN response by human immune cells
AU - Petzke, Mary M.
AU - Brooks, Andrew
AU - Krupna, Michelle A.
AU - Mordue, Dana
AU - Schwartz, Ira
PY - 2009/10/15
Y1 - 2009/10/15
N2 - Borrelia burgdorferi is the spirochetal agent of Lyme disease, a multisystemic disorder characterized by inflammation. Using global transcriptional profiling, we characterized the response of human PBMCs exposed to B. burgdorferi in an ex vivo coculture system. The expression profiles induced by B. burgdorferi were marked by the intense up-regulation of IFN-responsive transcripts and transcripts involved in the JAK/STAT signaling pathway. Transcript levels of IFN-α, IFN-β, and IRF7, and protein concentrations of IFN-α, were significantly elevated relative to those in unstimulated PBMCs. The induction of IFN-α was completely dependent upon phagocytosis of B. burgdorferi. Addition of a soluble type I IFN receptor, B18R, did not abolish the induction of IFN-inducible genes, indicating that B. burgdorferi directly elicits enhanced expression of these genes independently of type I IFN feedback signaling. Inhibitors of either TLR7 or TLR9 significantly reduced B. burgdorferi-stimulated IFN-α protein expression and transcription of IFN-induced genes. Simultaneous inhibition of both TLR7 and TLR9 completely abrogated IFN-α induction. The IFN-α-producing populations in PBMCs were identified as plasmacytoid dendritic and CD14 +CD11c+ cells. These results reveal a TLR7/9-dependent signaling pathway used by human PBMCs to initiate a type I IFN response to the extracellular bacterium B. burgdorferi.
AB - Borrelia burgdorferi is the spirochetal agent of Lyme disease, a multisystemic disorder characterized by inflammation. Using global transcriptional profiling, we characterized the response of human PBMCs exposed to B. burgdorferi in an ex vivo coculture system. The expression profiles induced by B. burgdorferi were marked by the intense up-regulation of IFN-responsive transcripts and transcripts involved in the JAK/STAT signaling pathway. Transcript levels of IFN-α, IFN-β, and IRF7, and protein concentrations of IFN-α, were significantly elevated relative to those in unstimulated PBMCs. The induction of IFN-α was completely dependent upon phagocytosis of B. burgdorferi. Addition of a soluble type I IFN receptor, B18R, did not abolish the induction of IFN-inducible genes, indicating that B. burgdorferi directly elicits enhanced expression of these genes independently of type I IFN feedback signaling. Inhibitors of either TLR7 or TLR9 significantly reduced B. burgdorferi-stimulated IFN-α protein expression and transcription of IFN-induced genes. Simultaneous inhibition of both TLR7 and TLR9 completely abrogated IFN-α induction. The IFN-α-producing populations in PBMCs were identified as plasmacytoid dendritic and CD14 +CD11c+ cells. These results reveal a TLR7/9-dependent signaling pathway used by human PBMCs to initiate a type I IFN response to the extracellular bacterium B. burgdorferi.
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U2 - 10.4049/jimmunol.0901390
DO - 10.4049/jimmunol.0901390
M3 - Article
C2 - 19794067
SN - 0022-1767
VL - 183
SP - 5279
EP - 5292
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -