A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP.
The innate immune system responds to unique molecular signatures that are widely conserved among microbes but that are not normally present in host cells. Compounds that stimulate innate immune pathways may be valuable in the design of novel adjuvants, vaccines, and other immunotherapeutics. The cyclic dinucleotide cyclic-di-guanosine monophosphate (c-di-GMP) is a recently appreciated second messenger that plays critical regulatory roles in many species of bacteria but is not produced by eukaryotic cells. In vivo and in vitro studies have previously suggested that c-di-GMP is a potent immunostimulatory compound recognized by mouse and human cells. We provide evidence that c-di-GMP is sensed in the cytosol of mammalian cells via a novel immunosurveillance pathway. The potency of cytosolic signaling induced by c-di-GMP is comparable to that induced by cytosolic delivery of DNA, and both nucleic acids induce a similar transcriptional profile, including triggering of type I interferons and coregulated genes via induction of TBK1, IRF3, nuclear factor kappaB, and MAP kinases. However, the cytosolic pathway that senses c-di-GMP appears to be distinct from all known nucleic acid-sensing pathways. Our results suggest a novel mechanism by which host cells can induce an inflammatory response to a widely produced bacterial ligand.
McWhirter
Sarah M
SM
Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, CA 94720, USA. mcwhirt@berkeley.edu
Barbalat
Roman
R
Monroe
Kathryn M
KM
Fontana
Mary F
MF
Hyodo
Mamoru
M
Joncker
Nathalie T
NT
Ishii
Ken J
KJ
Akira
Shizuo
S
Colonna
Marco
M
Chen
Zhijian J
ZJ
Fitzgerald
Katherine A
KA
Hayakawa
Yoshihiro
Y
Vance
Russell E
RE
D000818:Animals; D045744:Cell Line, Tumor; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism; D003600:Cytosol / Q000276:immunology / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D015151:Immunoblotting; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D015290:Second Messenger Systems / Q000276:immunology*
D017931:DNA Primers; D007370:Interferon Type I; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP