title: Bacterial c-di-GMP is an immunostimulatory molecule.
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.
authors.affiliation: Intragenics Research Institute, Havre de Grace, MD 21078, USA. dkaraolis@intragenics.org
authors.forename: David K R
authors.initials: DK
authors.lastname: Karaolis
authors.forename: Terry K
authors.initials: TK
authors.lastname: Means
authors.forename: De
authors.initials: D
authors.lastname: Yang
authors.forename: Munehisa
authors.initials: M
authors.lastname: Takahashi
authors.forename: Teizo
authors.initials: T
authors.lastname: Yoshimura
authors.forename: Eric
authors.initials: E
authors.lastname: Muraille
authors.forename: Dana
authors.initials: D
authors.lastname: Philpott
authors.forename: John T
authors.initials: JT
authors.lastname: Schroeder
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hyodo
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Brian G
authors.initials: BG
authors.lastname: Talbot
authors.forename: Eric
authors.initials: E
authors.lastname: Brouillette
authors.forename: François
authors.initials: F
authors.lastname: Malouin
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000917:Antibody Formation / Q000187:drug effects* / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D002478:Cells, Cultured; D003030:Coagulase / Q000276:immunology / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D005260:Female; D006098:Granulocytes / Q000276:immunology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D009000:Monocytes / Q000276:immunology; D019707:Receptors, Chemokine / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology* / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000276:immunology*; D014611:Vaccination; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D015703:Antigens, CD; D001426:Bacterial Proteins; C515944:ClfA protein, Staphylococcus aureus; D003030:Coagulase; D016207:Cytokines; D019707:Receptors, Chemokine; C062025:bis(3',5')-cyclic diguanylic acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006152:Cyclic GMP