Host Immune Response to Bacterial Cyclic Diguanylic Acid (c-di-GMP)

Abstract : This work tested the hypothesis that c-di-GMP is a novel immunostimulatory molecule that modulates the immune response. Intramammary treatment of mice with c-di-GMP before S. aureus challenge gave a protective effect and a 1O,OOO-fold reduction in CFUs in tissues. 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 titer 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-g, IL-8, MCP-l, IFN-g-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. We found that c-di-GMP activates ERK phosphorylation in human M-CSF-induced monocyte-derived macrophages , c-di-GMP is stable in human serum. We have also found that c-di-GMP acts as a potent adjuvant in vaccine studies in vivo to inhibit infection by MRSA, Streptococcus pneumoniae, and Klebsiella pneumoniae. We propose c-di-GMP can be used clinically as an immunomodulator, immune enhancer, or vaccine adjuvant.