Bacterial c-di-GMP is an immunostimulatory molecule

David K R Karaolis, Terry K. Means, De Yang, Munehisa Takahashi, Teizo Yoshimura, Eric Muraille, Dana Philpott, John Thomas Schroeder, Mamoru Hyodo, Yoshihiro Hayakawa, Brian G. Talbot, Eric Brouillette, François Malouin

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Abstract

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-γ, IL-8, MCP-1, IFN-γ-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.

Original languageEnglish (US)
Pages (from-to)2171-2181
Number of pages11
JournalJournal of Immunology
Volume178
Issue number4
Publication statusPublished - Feb 15 2007

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ASJC Scopus subject areas

  • Immunology

Cite this

Karaolis, D. K. R., Means, T. K., Yang, D., Takahashi, M., Yoshimura, T., Muraille, E., ... Malouin, F. (2007). Bacterial c-di-GMP is an immunostimulatory molecule. Journal of Immunology, 178(4), 2171-2181.