A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP
Sarah M. McWhirter, Roman Barbalat, Kathryn M. Monroe, Mary F. Fontana, Mamoru Hyodo, Nathalie T. Joncker, Ken J. Ishii, Shizuo Akira, Marco Colonna, Zhijian J. Chen, Katherine A. Fitzgerald, Yoshihiro Hayakawa, Russell E. Vance
Center For Genetics Of Host Defense
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 κB, 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.
https://doi.org/10.1084/jem.20082874
Interferon Type I
Cyclic GMP
Second Messenger Systems
Immunologic Monitoring
Eukaryotic Cells
bis(3',5')-cyclic diguanylic acid
McWhirter, S. M., Barbalat, R., Monroe, K. M., Fontana, M. F., Hyodo, M., Joncker, N. T., ... Vance, R. E. (2009). A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP. Journal of Experimental Medicine, 206(9), 1899-1911. https://doi.org/10.1084/jem.20082874
A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP. / McWhirter, Sarah M.; Barbalat, Roman; Monroe, Kathryn M.; Fontana, Mary F.; Hyodo, Mamoru; Joncker, Nathalie T.; Ishii, Ken J.; Akira, Shizuo; Colonna, Marco; Chen, Zhijian J.; Fitzgerald, Katherine A.; Hayakawa, Yoshihiro; Vance, Russell E.
In: Journal of Experimental Medicine, Vol. 206, No. 9, 31.08.2009, p. 1899-1911.
McWhirter, SM, Barbalat, R, Monroe, KM, Fontana, MF, Hyodo, M, Joncker, NT, Ishii, KJ, Akira, S, Colonna, M, Chen, ZJ, Fitzgerald, KA, Hayakawa, Y & Vance, RE 2009, 'A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP', Journal of Experimental Medicine, vol. 206, no. 9, pp. 1899-1911. https://doi.org/10.1084/jem.20082874
McWhirter SM, Barbalat R, Monroe KM, Fontana MF, Hyodo M, Joncker NT et al. A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP. Journal of Experimental Medicine. 2009 Aug 31;206(9):1899-1911. https://doi.org/10.1084/jem.20082874
McWhirter, Sarah M. ; Barbalat, Roman ; Monroe, Kathryn M. ; Fontana, Mary F. ; Hyodo, Mamoru ; Joncker, Nathalie T. ; Ishii, Ken J. ; Akira, Shizuo ; Colonna, Marco ; Chen, Zhijian J. ; Fitzgerald, Katherine A. ; Hayakawa, Yoshihiro ; Vance, Russell E. / A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP. In: Journal of Experimental Medicine. 2009 ; Vol. 206, No. 9. pp. 1899-1911.
@article{2e132214f6bb444583cfde353ef56e6e,
title = "A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP",
abstract = "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 κB, 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.",
author = "McWhirter, {Sarah M.} and Roman Barbalat and Monroe, {Kathryn M.} and Fontana, {Mary F.} and Mamoru Hyodo and Joncker, {Nathalie T.} and Ishii, {Ken J.} and Shizuo Akira and Marco Colonna and Chen, {Zhijian J.} and Fitzgerald, {Katherine A.} and Yoshihiro Hayakawa and Vance, {Russell E.}",
doi = "10.1084/jem.20082874",
journal = "Journal of Experimental Medicine",
publisher = "Rockefeller University Press",
T1 - A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP
AU - McWhirter, Sarah M.
AU - Barbalat, Roman
AU - Monroe, Kathryn M.
AU - Fontana, Mary F.
AU - Hyodo, Mamoru
AU - Joncker, Nathalie T.
AU - Ishii, Ken J.
AU - Akira, Shizuo
AU - Colonna, Marco
AU - Chen, Zhijian J.
AU - Fitzgerald, Katherine A.
AU - Hayakawa, Yoshihiro
AU - Vance, Russell E.
N2 - 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 κB, 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.
AB - 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 κB, 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.
U2 - 10.1084/jem.20082874
DO - 10.1084/jem.20082874
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
10.1084/jem.20082874