Sublingual targeting of STING with 3'3'-cGAMP promotes systemic and mucosal immunity against anthrax toxins.
Anthrax is caused by Bacillus anthracis, a zoonotic bacterial pathogen affecting humans and livestock worldwide. The current human anthrax vaccine, anthrax vaccine adsorbed (AVA), is an injected vaccine with a cumbersome administration schedule and fails to promote mucosal immunity. Bacterial enterotoxins, which stimulate production of the cyclic nucleotide cAMP are effective experimental mucosal vaccine adjuvants, but their inherent toxicity has precluded their use in humans. We investigated whether cyclic dinucleotides that target Stimulator of Interferon Gamma Genes (STING) in mammalian cells could represent an alternative to bacterial enterotoxins as adjuvant for sublingual immunization and promotion of mucosal immunity and secretory IgA responses in addition to systemic immunity. We found that sublingual immunization of mice with Bacillus anthracis protective antigen (PA) and the STING ligand 3'3'-cGAMP promotes PA-specific serum IgG Ab responses of the same magnitude as those induced after immunization with PA and the experimental adjuvant cholera toxin (CT). Interestingly, this STING ligand also promoted serum anti-PA IgA and IgA-producing cells in the bone marrow. Furthermore, the saliva of mice immunized with the STING ligand exhibited similar levels of PA-specific IgA Abs as groups immunized with CT as adjuvant. The adjuvant activity of 3'3'-cGAMP was associated with mixed Th1, Th2, and Th17 responses. This STING ligand also induced rapid IFN-β and IL-10 responses in sublingual tissues and cervical lymph nodes, and TGF-β responses in the cervical lymph nodes, which could contribute to promoting IgA responses after sublingual immunization.
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States.
Tara L
TL
Martin
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States.
Junbae
J
Jee
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States.
Eunsoo
E
Kim
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States.
Haley E
HE
Steiner
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States.
Estelle
E
Cormet-Boyaka
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States. Electronic address: boyaka.1@osu.edu.
Prosper N
PN
Boyaka
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000286:Administration, Sublingual; D000818:Animals; D022122:Anthrax Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D000992:Antitoxins / Q000097:blood; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000032:analysis / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009712:Nucleotides, Cyclic / Q000008:administration & dosage*; D012463:Saliva / Q000276:immunology; D000099197:STING Protein
D000276:Adjuvants, Immunologic; D022122:Anthrax Vaccines; D000942:Antigens, Bacterial; D000992:Antitoxins; D001427:Bacterial Toxins; D016207:Cytokines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; C530855:Sting1 protein, mouse; D000099197:STING Protein; C030325:anthrax toxin; C584311:cyclic guanosine monophosphate-adenosine monophosphate
Mucosal; Mucosal adjuvant; STING; Sublingual