Bacterial c-di-GMP is an immunostimulatory molecule

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...

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Bibliographic Details
Published in:Journal of Immunology Vol. 178; no. 4; pp. 2171 - 2181
Main Authors: Karaolis, David K R, Means, Terry K, Yang, De, Takahashi, Munehisa, Yoshimura, Teizo, Muraille, Eric, Philpott, Dana, Schroeder, John T, Hyodo, Mamoru, Hayakawa, Yoshihiro, Talbot, Brian G, Brouillette, Eric, Malouin, François
Format: Journal Article
Language:English
Published: United States 15.02.2007
Subjects:
Adjuvants, Immunologic - pharmacology
Animals
Antibodies, Bacterial - immunology
Antibody Formation - drug effects
Antibody Formation - immunology
Antigens, CD - immunology
Bacterial Proteins - immunology
Cells, Cultured
Coagulase - immunology
Coagulase - pharmacology
Cyclic GMP - analogs & derivatives
Cyclic GMP - immunology
Cyclic GMP - pharmacology
Cytokines - immunology
Dendritic Cells - immunology
Disease Models, Animal
Extracellular Signal-Regulated MAP Kinases - immunology
Female
Granulocytes - immunology
Humans
Macrophage Activation - drug effects
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - immunology
Mice
Monocytes - immunology
p38 Mitogen-Activated Protein Kinases - immunology
Receptors, Chemokine - immunology
Staphylococcal Infections - immunology
Staphylococcal Infections - prevention & control
Staphylococcus aureus
Staphylococcus aureus - immunology
Vaccination
ISSN:0022-1767, 1365-2567
Online Access:Get full text
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Summary: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.
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ISSN:0022-1767
1365-2567
DOI:10.4049/jimmunol.178.4.2171