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* Intragenics Research Institute, Havre de Grace, MD 21078;
Karagen Pharmaceuticals, Baltimore, MD 21210;
Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD 21201;
Center for Immunology and Inflammatory Diseases, Harvard University, MA 02129;
¶ Center for Cancer Research and
|| Laboratory of Molecular Immunoregulation, National Cancer Institute at Frederick, Frederick, MD 21702;
# Faculté de Médecine, Université Libre de Bruxelles, Belgique;
** Department of Immunology, University of Toronto, Toronto, Ontario, Canada;
Department of Medicine, Johns Hopkins University, Baltimore, MD 21224;
* Graduate School of Information Science, Nagoya University, Nagoya, Japan; and
* Département de Biologie, Université de Sherbrooke, Sherbrooke, Quebec, Canada
Cyclic diguanylate (c-di-GMP) is a bacterial intracellular signaling molecule. We have shown that treatment with exogenous c-di-GMP inhibits Staphylococcus aureus infection in a mouse model. We now report that c-di-GMP is an immodulator and immunostimulatory molecule. Intramammary treatment of mice with c-di-GMP 12 and 6 h before S. aureus challenge gave a protective effect and a 10,000-fold reduction in CFUs in tissues (p < 0.001). Intramuscular vaccination of mice with c-di-GMP coinjected with S. aureus clumping factor A (ClfA) Ag produced serum with significantly higher anti-ClfA IgG Ab titers (p < 0.001) compared with ClfA alone. Intraperitoneal injection of mice with c-di-GMP activated monocyte and granulocyte recruitment. Human immature dendritic cells (DCs) cultured in the presence of c-di-GMP showed increased expression of costimulatory molecules CD80/CD86 and maturation marker CD83, increased MHC class II and cytokines and chemokines such as IL-12, IFN-
, IL-8, MCP-1, IFN--inducible protein 10, and RANTES, and altered expression of chemokine receptors including CCR1, CCR7, and CXCR4. c-di-GMP-matured DCs demonstrated enhanced T cell stimulatory activity. c-di-GMP activated p38 MAPK in human DCs and ERK phosphorylation in human macrophages. c-di-GMP is stable in human serum. We propose that cyclic dinucleotides like c-di-GMP can be used clinically in humans and animals as an immunomodulator, immune enhancer, immunotherapeutic, immunoprophylactic, or vaccine adjuvant.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grant MOP-57701 (to F.M.) from the Canadian Institute for Health Research. D.K.R.K. is a recipient of a Burroughs Wellcome Fund Career Award in the Biomedical Sciences. E.M. is a Research Associate from the Fonds National de la Recherche Scientifique.
2 Address correspondence and reprint requests to Dr. David K. R. Karaolis, Intragenics Research Institute, 415 Oakington Road, Havre de Grace, MD 21078. E-mail address: dkaraolis{at}intragenics.org
3 Abbreviations used in this paper: c-di-GMP, cyclic diguanylate; DC, dendritic cell; pDC, plasmacytoid cell; ClfA, clumping factor A; ODN, oligodeoxynucleotide; QPCR, quantitative PCR; MFI, mean fluorescent intensity; Nod, nucleotide-binding oligomerization domain; HEK, human embryonic kidney.
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