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¹ Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, CA 94720
² Laboratory of Bioorganic Chemistry, Graduate School of Information Science, Nagoya University, Chikusa, Nagoya 464-8601, Japan
³ Laboratory of Host Defense, World Premier International Research Center, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan
⁴ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
⁵ Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
⁶ Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605

CORRESPONDENCE Sarah M. McWhirter: mcwhirt{at}berkeley.edu OR Russell E. Vance: rvance{at}berkeley.edu

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 B, 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.

Abbreviations used: c-di-GMP, cyclic-di-GMP; DAI, DNA-dependent activator of IFN regulatory factors; HSA, human serum albumin; MEF, mouse embryonic fibroblast; TLR, Toll-like receptor.

© 2009 McWhirter et al.
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