title: c-di-GMP as a vaccine adjuvant enhances protection against systemic methicillin-resistant Staphylococcus aureus (MRSA) infection.
abstract: Cyclic diguanylate (c-di-GMP) is a novel immunomodulator and immune enhancer that triggers a protective host innate immune response. The protective effect of c-di-GMP as a vaccine adjuvant against Staphylococcus aureus infection was investigated by subcutaneous (s.c.) vaccination with two different S. aureus antigens, clumping factor A (ClfA) and a nontoxic mutant staphylococcal enterotoxin C (mSEC), then intravenous (i.v.) challenge with viable methicillin-resistant S. aureus (MRSA) in a systemic infection model. Mice immunized with c-di-GMP plus mSEC or c-di-GMP plus ClfA vaccines then challenged with MRSA produced strong antigen-specific antibody responses demonstrating immunogenicity of the vaccines. Bacterial counts in the spleen and liver of c-di-GMP plus mSEC and c-di-GMP plus ClfA-immunized mice were significantly lower than those of control mice (P<0.001). Mice immunized with c-di-GMP plus mSEC or c-di-GMP plus ClfA showed significantly higher survival rates at day 7 (87.5%) than those of the non-immunized control mice (33.3%) (P<0.05). Furthermore, immunization of mice with c-di-GMP plus mSEC or c-di-GMP plus ClfA induced not only very high titers of immunoglobulin G1 (IgG1), but c-di-GMP plus mSEC also induced significantly higher levels of IgG2a, IgG2b and IgG3 compared to alum adjuvant (P<0.01 and P<0.001, respectively) and c-di-GMP plus ClfA induced significantly higher levels of IgG2a, IgG2b and IgG3 compared to alum adjuvant (P<0.001). Our results show that c-di-GMP should be developed as an adjuvant and immunotherapeutic to provide protection against systemic infection caused by S. aureus (MRSA).
authors.affiliation: Department of Microbiology and Immunology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Dong-Liang
authors.initials: DL
authors.lastname: Hu
authors.forename: Kouji
authors.initials: K
authors.lastname: Narita
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hyodo
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Akio
authors.initials: A
authors.lastname: Nakane
authors.forename: David K R
authors.initials: DK
authors.lastname: Karaolis
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000534:Alum Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D003030:Coagulase / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D015169:Colony Count, Microbial; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004768:Enterotoxins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007279:Injections, Subcutaneous; D008099:Liver / Q000382:microbiology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000382:microbiology; D013203:Staphylococcal Infections / Q000517:prevention & control*; D013209:Staphylococcal Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; C515944:ClfA protein, Staphylococcus aureus; D003030:Coagulase; D004768:Enterotoxins; D007074:Immunoglobulin G; D013209:Staphylococcal Vaccines; C041524:aluminum sulfate; C034959:enterotoxin C, staphylococcal; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP