title: Enhanced immunostimulatory activity of cyclic dinucleotides on mouse cells when complexed with a cell-penetrating peptide or combined with CpG.
abstract: Recognition of pathogen-derived nucleic acids by immune cells is critical for the activation of protective innate immune responses. Bacterial cyclic dinucleotides (CDNs) are small nucleic acids that are directly recognized by the cytosolic DNA sensor STING (stimulator of IFN genes), initiating a response characterized by proinflammatory cytokine and type I IFN production. Strategies to improve the immune stimulatory activities of CDNs can further their potential for clinical development. Here, we demonstrate that a simple complex of cylic-di-GMP with a cell-penetrating peptide enhances both cellular delivery and biological activity of the cyclic-di-GMP in murine splenocytes. Furthermore, our findings establish that activation of the TLR-dependent and TLR-independent DNA recognition pathways through combined use of CpG oligonucleotide (ODN) and CDN results in synergistic activity, augmenting cytokine production (IFN-α/β, IL-6, TNF-α, IP-10), costimulatory molecule upregulation (MHC class II, CD86), and antigen-specific humoral and cellular immunity. Results presented herein indicate that 3'3'-cGAMP, a recently identified bacterial CDN, is a superior stimulator of IFN genes ligand than cyclic-di-GMP in human PBMCs. Collectively, these findings suggest that the immune-stimulatory properties of CDNs can be augmented through peptide complexation or synergistic use with CpG oligonucleotide and may be of interest for the development of CDN-based immunotherapeutic agents.
authors.affiliation: Department of Biological Sciences, Middle East Technical University, Ankara, Turkey.
authors.forename: Soner
authors.initials: S
authors.lastname: Yildiz
authors.forename: Esin
authors.initials: E
authors.lastname: Alpdundar
authors.forename: Bilgi
authors.initials: B
authors.lastname: Gungor
authors.forename: Tamer
authors.initials: T
authors.lastname: Kahraman
authors.forename: Banu
authors.initials: B
authors.lastname: Bayyurt
authors.forename: Ihsan
authors.initials: I
authors.lastname: Gursel
authors.forename: Mayda
authors.initials: M
authors.lastname: Gursel
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D057846:Cell-Penetrating Peptides / Q000494:pharmacology*; D018899:CpG Islands; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007370:Interferon Type I / Q000096:biosynthesis; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009712:Nucleotides, Cyclic / Q000494:pharmacology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000099197:STING Protein
chemical_list: D000276:Adjuvants, Immunologic; D057846:Cell-Penetrating Peptides; D006152:Cyclic GMP; D016207:Cytokines; D007370:Interferon Type I; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D009838:Oligodeoxyribonucleotides; D010455:Peptides; C408982:CPG-oligonucleotide; C530855:Sting1 protein, mouse; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C062025:bis(3',5')-cyclic diguanylic acid
keywords: Arginine peptide (nona-arginine); CpG ODN; Cyclic-di-GMP; Immunostimulation; cGAMP