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 T. Schroeder, Mamoru Hyodo, Yoshihiro Hayakawa, Brian G. Talbot, Eric Brouillette, François Malouin

Research output: Contribution to journalArticle

156 Citations (Scopus)

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
Pages (from-to)2171-2181
Number of pages11
JournalJournal of Immunology
Volume178
Issue number4
DOIs
Publication statusPublished - Feb 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Karaolis, D. K. R., Means, T. K., Yang, D., Takahashi, M., Yoshimura, T., Muraille, E., Philpott, D., Schroeder, J. T., Hyodo, M., Hayakawa, Y., Talbot, B. G., Brouillette, E., & Malouin, F. (2007). Bacterial c-di-GMP is an immunostimulatory molecule. Journal of Immunology, 178(4), 2171-2181. https://doi.org/10.4049/jimmunol.178.4.2171