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

Research output: Contribution to journalArticle

196 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1899-1911
Number of pages13
JournalJournal of Experimental Medicine
Volume206
Issue number9
DOIs
StatePublished - Aug 31 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    McWhirter, S. M., Barbalat, R., Monroe, K. M., Fontana, M. F., Hyodo, M., Joncker, N. T., Ishii, K. J., Akira, S., Colonna, M., Chen, Z. J., Fitzgerald, K. A., Hayakawa, Y., & 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