C-di-GMP is an effective immunomodulator and vaccine adjuvant against pneumococcal infection

TY - JOUR

T1 - C-di-GMP is an effective immunomodulator and vaccine adjuvant against pneumococcal infection

AU - Ogunniyi, Abiodun D.

AU - Paton, James C.

AU - Kirby, Alun C.

AU - McCullers, Jonathan A.

AU - Cook, Jan

AU - Hyodo, Mamoru

AU - Hayakawa, Yoshihiro

AU - Karaolis, David K. R.

PY - 2008/8/26

Y1 - 2008/8/26

N2 - 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 all effective broad spectrum immunomodulator and vaccine adjuvant to prevent infectious diseases. (C) 2008 Elsevier Ltd. All rights reserved.

AB - 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 all effective broad spectrum immunomodulator and vaccine adjuvant to prevent infectious diseases. (C) 2008 Elsevier Ltd. All rights reserved.

KW - Streptococcus pneumoniae

KW - c-di-GMP

KW - immunomodulator

KW - adjuvant

KW - vaccine

KW - CYCLIC DIGUANYLIC ACID

KW - KILLER T-CELLS

KW - PROTEIN-A PSPA

KW - STREPTOCOCCUS-PNEUMONIAE

KW - STAPHYLOCOCCUS-AUREUS

KW - CELLULOSE SYNTHESIS

KW - SURFACE PROTEIN

KW - ALVEOLAR MACROPHAGES

KW - ACETOBACTER-XYLINUM

KW - BACTERIAL CLEARANCE

UR - http://www.scopus.com/inward/record.url?scp=48649084066&partnerID=8YFLogxK

U2 - 10.1016/j.vaccine.2008.06.099

DO - 10.1016/j.vaccine.2008.06.099

M3 - Article

SN - 0264-410X

VL - 26

SP - 4676

EP - 4685

JO - Vaccine

JF - Vaccine

IS - 36

ER -