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Bacterial c-di-GMP is an immunostimulatory molecule

  1. Author:
    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.

  2. Author Address

    Intragen Res Inst, Havre De Grace, MD 21078 USA. Karagen Pharmaceut, Baltimore, MD 21210 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Harvard Univ, Ctr Immunol & Inflammatory Dis, Boston, MA 02129 USA. NCI, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. Univ Libre Bruxelles, Fac Med, Brussels, Belgium. Univ Toronto, Dept Immunol, Toronto, ON, Canada. Johns Hopkins Univ, Dept Med, Baltimore, MD 21224 USA. Nagoya Univ, Grad Sch Informat Sci, Nagoya, Aichi, Japan. Univ Sherbrooke, Dept Biol, Sherbrooke, PQ J1K 2R1, Canada.;Karaolis, DKR, Intragen Res Inst, 415 Oakington Rd, Havre De Grace, MD 21078 USA.;dkaraolis@intragenics.org
    1. Year: 2007
    2. Date: Feb
  2. Journal: Journal of Immunology
    1. 178
    2. 4
    3. Pages: 2171-2181
  4. Type of Article: Article
  5. ISSN: 0022-1767
  1. 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-gamma, IL-8, MCP-1, IFN-gamma-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 Journal of Immunology, 2007, 178: 2171-2181.

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  1. View record in Web of Science®
  2. WOS: 000244026800024

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