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: Abiodun D Ogunniyi, James C Paton, Alun C Kirby, Jonathan A McCullers, Jan Cook, Mamoru Hyodo, Yoshihiro Hayakawa, David K R Karaolis
• Journal: Vaccine (Vaccine) Vol. 26 Issue 36 Pg. 4676-85 (Aug 26 2008) ISSN: 0264-410X [Print] Netherlands
• PMID: 18640167 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Alum Compounds
• Antibodies, Bacterial
• Bacterial Proteins
• Immunologic Factors
• Pneumococcal Vaccines
• Streptolysins
• plY protein, Streptococcus pneumoniae
• pneumococcal surface protein A
• aluminum sulfate
• bis(3',5')-cyclic diguanylic acid
• Cyclic GMP

Topics

• Adjuvants, Immunologic (administration & dosage, pharmacology)
• Administration, Intranasal
• Alum Compounds (administration & dosage)
• Animals
• Antibodies, Bacterial (blood)
• Bacterial Proteins (immunology)
• Blood (microbiology)
• Colony Count, Microbial
• Cyclic GMP (analogs & derivatives, pharmacology)
• Female
• Immunologic Factors (administration & dosage, pharmacology)
• Injections, Intraperitoneal
• Lung (immunology, microbiology)
• Lymph Nodes (immunology)
• Male
• Mice
• Mice, Inbred BALB C
• Pneumococcal Infections (prevention & control)
• Pneumococcal Vaccines (immunology)
• Streptococcus pneumoniae (growth & development, immunology)
• Streptolysins (immunology)
• Survival Analysis