title: c-di-GMP is an effective immunomodulator and vaccine adjuvant against pneumococcal infection.
abstract: Cyclic diguanylate (c-di-GMP) is a unique bacterial intracellular signaling molecule capable of stimulating enhanced protective innate immunity against various bacterial infections. The effects of intranasal pretreatment with c-di-GMP, or intraperitoneal coadministration of c-di-GMP with the pneumolysin toxoid (PdB) or pneumococcal surface protein A (PspA) before pneumococcal challenge, were investigated in mice. We found that c-di-GMP had no significant direct short-term effect on the growth rate of Streptococcus pneumoniae either in vitro or in vivo. However, intranasal pretreatment of mice with c-di-GMP resulted in a significant decrease in bacterial load in lungs and blood after serotypes 2 and 3 challenge, and a significant decrease in lung titers after serotype 4 challenge. Potential cellular mediators of these enhanced protective responses were identified in lungs and draining lymph nodes. Intraperitoneal coadministration of c-di-GMP with PdB or PspA before challenge resulted in significantly higher antigen-specific antibody titers and increased survival of mice, compared to that obtained with alum adjuvant. These findings demonstrate that local or systemic c-di-GMP administration stimulates innate and adaptive immunity against invasive pneumococcal disease. We propose that c-di-GMP can be used as an effective broad spectrum immunomodulator and vaccine adjuvant to prevent infectious diseases.
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, South Australia 5005, Australia.
authors.forename: Abiodun D
authors.initials: AD
authors.lastname: Ogunniyi
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.forename: Alun C
authors.initials: AC
authors.lastname: Kirby
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: McCullers
authors.forename: Jan
authors.initials: J
authors.lastname: Cook
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hyodo
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: David K R
authors.initials: DK
authors.lastname: Karaolis
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000281:Administration, Intranasal; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001426:Bacterial Proteins / Q000276:immunology; D001769:Blood / Q000382:microbiology; D015169:Colony Count, Microbial; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011008:Pneumococcal Infections / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000254:growth & development / Q000276:immunology; D013301:Streptolysins / Q000276:immunology; D016019:Survival Analysis
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D007155:Immunologic Factors; D022242:Pneumococcal Vaccines; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; C051592:pneumococcal surface protein A; C041524:aluminum sulfate; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP