title: The Vaccine Adjuvant Chitosan Promotes Cellular Immunity via DNA Sensor cGAS-STING-Dependent Induction of Type I Interferons.
abstract: The cationic polysaccharide chitosan is an attractive candidate adjuvant capable of driving potent cell-mediated immunity, but the mechanism by which it acts is not clear. We show that chitosan promotes dendritic cell maturation by inducing type I interferons (IFNs) and enhances antigen-specific T helper 1 (Th1) responses in a type I IFN receptor-dependent manner. The induction of type I IFNs, IFN-stimulated genes and dendritic cell maturation by chitosan required the cytoplasmic DNA sensor cGAS and STING, implicating this pathway in dendritic cell activation. Additionally, this process was dependent on mitochondrial reactive oxygen species and the presence of cytoplasmic DNA. Chitosan-mediated enhancement of antigen specific Th1 and immunoglobulin G2c responses following vaccination was dependent on both cGAS and STING. These findings demonstrate that a cationic polymer can engage the STING-cGAS pathway to trigger innate and adaptive immune responses.
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Carroll
authors.affiliation: Centre for Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, MC 151, Albany, NY 12208, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Andres
authors.initials: A
authors.lastname: Mori
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Muñoz-Wolf
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Oleszycka
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Hannah B T
authors.initials: HBT
authors.lastname: Moran
authors.affiliation: Centre for Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, MC 151, Albany, NY 12208, USA.
authors.forename: Samira
authors.initials: S
authors.lastname: Mansouri
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Craig P
authors.initials: CP
authors.lastname: McEntee
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Eimear
authors.initials: E
authors.lastname: Lambe
authors.affiliation: Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, 2300 Copenhagen S, Denmark.
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Agger
authors.affiliation: Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, 2300 Copenhagen S, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.affiliation: School of Biochemistry and Immunology and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Colm
authors.initials: C
authors.lastname: Cunningham
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, MIMR-PHI and Department of Molecular and Translational Sciences, Monash University, Clayton, VIC 3068, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Hertzog
authors.affiliation: Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA; Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Viral Immune Evasion Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bowie
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland; Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN) & Advanced Materials Bio-Engineering Research Centre (AMBER), Trinity College Dublin, Dublin 2, D02 PN40, Ireland. Electronic address: lavellee@tcd.ie.
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement; D002478:Cells, Cultured; D048271:Chitosan / Q000008:administration & dosage*; D004247:DNA / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D007074:Immunoglobulin G / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D014612:Vaccines / Q000008:administration & dosage; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D000276:Adjuvants, Immunologic; D048271:Chitosan; D004247:DNA; D007074:Immunoglobulin G; D007370:Interferon Type I; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D017382:Reactive Oxygen Species; D014612:Vaccines; C532857:STING1 protein, human; D000099197:STING Protein; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase