Nucleotides are essential components of living organisms. From genetic information storage to energy production, nucleotides in various forms are central to many fundamental physiological processes. Second messenger signaling is a critical part of many important biological systems – amplifying signals to trigger rapid downstream responses. Cyclic nucleotides as second messenger molecules are important in the control of homeostasis, intracellular responses to extracellular cues, and the immune system (Fig. 1). Perhaps the most well-known and best studied cyclic nucleotides are the cyclic purine mononucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). cAMP and cGMP are nearly ubiquitous second messengers and many processes in metabolism, inflammation, and disease are regulated by these molecules, highlighting their potential in therapeutic development. Due to the extent at which cAMP and cGMP are used by cells to control a multitude of important biological activities, off-target effects have posed a major challenge with developing effective therapeutic strategies for treatment of conditions related to the function of these molecules. This is especially true for targeting cAMP and cGMP signaling in the context of immunity which necessitates cell-type specificity and if this is not achieved then systemic activation or inhibition of these pathways could be detrimental to patient health.

While known for many decades to play important physiological roles, the involvement of specialized cyclic nucleotide signals in the innate immune system is a rather recent finding. The innate immune system represents the first line of defense against pathogens but can be thought of more broadly as a mechanism to maintain status quo via detection of normal self versus abnormal non-self. In recent years, the discovery of cyclic dinucleotides (CDNs) controlling immunity in humans has opened many new avenues in the treatment of disease. cGAS–STING signaling through the unique CDN 2′3′-cGAMP (2′-5′/3′-5′-cyclic guanosine monophosphate-adenosine monophosphate) is of known importance to human health as it controls immune responses to viruses, bacterial pathogens, cancer, and other cellular defects. With such a centralized role in immunity, there has been a great deal of attention to targeting the cGAS–STING pathway in treatment of several human diseases and conditions.

CDNs employed as second messengers to control critical physiological processes is an evolutionarily conserved feature of living organisms extending back as far as bacteria and archaea. Cyclic-di-GMP and cyclic-di-AMP are found in various signaling networks in bacteria such as exopolysaccharide synthesis, motility, biofilm formation, osmoregulation, and controlling metabolism (Jenal, Reinders, & Lori, 2017; Whiteley et al., 2017; Witte, Hartung, Büttner, & Hopfner, 2008; Wright et al., 2020). Additionally, the roles of 3′3′-cGAMP and other CDNs in prokaryotes have been extensively reviewed recently (Purificação, Azevedo, Araujo, Souza, & Guzzo, 2020). In contrast to the diversity of CDNs in prokaryotes, CDN signaling in metazoans was thought to operate almost exclusively through 2′3’-cGAMP in the context of cGAS-STING signaling (Kranzusch et al., 2015; Margolis, Wilson, & Vance, 2017). However, new evidence now suggests a previously unappreciated expansion of antiviral CDN synthesizing enzymes and receptors in invertebrates rivaling the diversity seen in prokaryotes (Linder, 2010).

New computational platforms for biosynthetic gene cluster analysis have led to the discovery and identification of new pools of antiviral compounds including cyclic nucleotides hidden within diverse prokaryotes. The field of study involving antiviral responses in prokaryotes and the roles of cyclic nucleotide second messengers has exploded in the last five years leading to a number of ground-breaking discoveries including unusual molecules such as the cyclic pyrimidine mononucleotides, cyclic trinucleotides, and newly defined compounds derived from the degradation of NAD+. These pathways and molecules hold promise for human health as new directions to pursue alternative strategies for antibiotic development in the control of bacterial pathogens.

The focus of the review is on the pharmacological potential of interfering with diverse cyclic nucleotide signaling pathways in immunity from humans to bacteria. We will address features of the enzymes, receptors, and degradation machinery controlling cyclic nucleotide signaling with a special emphasis on the roles these molecules and pathways play in controlling immune responses.