Abstract
Cyclic dinucleotides (CDNs), originally discovered as bacterial second messengers, play critical roles in bacterial signal transduction, cellular processes, biofilm formation, and virulence. The finding that CDNs can trigger the innate immune response in eukaryotic cells through the stimulator of interferon genes (STING) signalling pathway has prompted the extensive research and development of CDNs as potential immunostimulators and novel molecular adjuvants for induction of systemic and mucosal innate and adaptive immune responses. In this review, we summarize the chemical structure, biosynthesis regulation, and the role of CDNs in enhancing the crosstalk between host innate and adaptive immune responses. We also discuss the strategies to improve the efficient delivery of CDNs and the recent advance and future challenges in the development of CDNs as potential adjuvants in prophylactic vaccines against infectious diseases and in therapeutic vaccines against cancers.
Highlights
Cyclic dinucleotides (CDNs), originally discovered as bacterial second messengers, play critical roles in bacterial signal transduction, cellular processes, biofilm formation, and virulence
Cyclic dinucleotides (CDNs), including bacterial second messengers bis-(30,50 )-cyclic diguanosine monophosphate (c-di-GMP) and bis-(30,50 )-cyclic diadenosine monophosphate (c-di-AMP), 30 50 -30 50 cyclic GMP-AMP (30 30 -cGAMP) produced by Vibrio cholerae, and metazoan second messenger 20 50 -30 50 cyclic GMP-AMP (20 30 -cGAMP, hereafter cGAMP), bind to an endoplasmic reticulum (ER)-associated sensor termed as a stimulator of interferon genes (STING) [1,2,3,4]
It iskinase well established that CDNs activatefactor innate immunity by directly to STING to induce the production of type I IFN and inflammatory cytokines via TANKbinding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) pathway (Figure 4)
Summary
In their investigation of the regulation of cellulose synthesis in Acetobacter xylinum ( classified as Gluconacetobacter xylinus), Benziman and co-workers discovered a cyclic oligonucleotide that appeared to be an activator of cellulose synthase [6,7]. The of c-di-GMP, c-di-AMP,c-di-GMP together attracted with the diadenylate cyclase until around when its roles as a bacterial second messenger recognized, activity of the nucleotide-binding domains of the DNA-integrity scanningwere protein. In the ensuing few years since its discovery, c-di-GMP attracted very little attention until around 2004/2005 when its roles as a bacterial second messenger were recognized, and the field quickly expanded with the potential of this cyclic dinucleotide and its analogs as immunostimulatory agents and vaccine adjuvants.
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