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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Vydáno v:	Journal of Immunology Ročník 178; číslo 4; s. 2171 - 2181
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 15.02.2007
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0022-1767 1365-2567
DOI:	10.4049/jimmunol.178.4.2171