tetano
Editor, Senior Moderator
J Immunol
. 2023 Mar 20;ji2300026.
doi: 10.4049/jimmunol.2300026. Online ahead of print.
A Small Molecule RIG-I Agonist Serves as an Adjuvant to Induce Broad Multifaceted Influenza Virus Vaccine Immunity
Emily A Hemann[SUP] 1 2 [/SUP], Megan L Knoll[SUP] 1 [/SUP], Courtney R Wilkins[SUP] 1 [/SUP], Caroline Subra[SUP] 3 [/SUP], Richard Green[SUP] 1 [/SUP], Adolfo García-Sastre[SUP] 4 5 6 [/SUP], Paul G Thomas[SUP] 7 [/SUP], Lydie Trautmann[SUP] 3 8 [/SUP], Renee C Ireton[SUP] 1 [/SUP], Yueh-Ming Loo[SUP] 1 [/SUP], Michael Gale[SUP] 1 [/SUP]
Affiliations
Abstract
Retinoic acid-inducible gene I (RIG-I) is essential for activating host cell innate immunity to regulate the immune response against many RNA viruses. We previously identified that a small molecule compound, KIN1148, led to the activation of IFN regulatory factor 3 (IRF3) and served to enhance protection against influenza A virus (IAV) A/California/04/2009 infection. We have now determined direct binding of KIN1148 to RIG-I to drive expression of IFN regulatory factor 3 and NF-κB target genes, including specific immunomodulatory cytokines and chemokines. Intriguingly, KIN1148 does not lead to ATPase activity or compete with ATP for binding but activates RIG-I to induce antiviral gene expression programs distinct from type I IFN treatment. When administered in combination with a vaccine against IAV, KIN1148 induces both neutralizing Ab and IAV-specific T cell responses compared with vaccination alone, which induces comparatively poor responses. This robust KIN1148-adjuvanted immune response protects mice from lethal A/California/04/2009 and H5N1 IAV challenge. Importantly, KIN1148 also augments human CD8+ T cell activation. Thus, we have identified a small molecule RIG-I agonist that serves as an effective adjuvant in inducing noncanonical RIG-I activation for induction of innate immune programs that enhance adaptive immune protection of antiviral vaccination.
. 2023 Mar 20;ji2300026.
doi: 10.4049/jimmunol.2300026. Online ahead of print.
A Small Molecule RIG-I Agonist Serves as an Adjuvant to Induce Broad Multifaceted Influenza Virus Vaccine Immunity
Emily A Hemann[SUP] 1 2 [/SUP], Megan L Knoll[SUP] 1 [/SUP], Courtney R Wilkins[SUP] 1 [/SUP], Caroline Subra[SUP] 3 [/SUP], Richard Green[SUP] 1 [/SUP], Adolfo García-Sastre[SUP] 4 5 6 [/SUP], Paul G Thomas[SUP] 7 [/SUP], Lydie Trautmann[SUP] 3 8 [/SUP], Renee C Ireton[SUP] 1 [/SUP], Yueh-Ming Loo[SUP] 1 [/SUP], Michael Gale[SUP] 1 [/SUP]
Affiliations
- PMID: 36939421
- DOI: 10.4049/jimmunol.2300026
Abstract
Retinoic acid-inducible gene I (RIG-I) is essential for activating host cell innate immunity to regulate the immune response against many RNA viruses. We previously identified that a small molecule compound, KIN1148, led to the activation of IFN regulatory factor 3 (IRF3) and served to enhance protection against influenza A virus (IAV) A/California/04/2009 infection. We have now determined direct binding of KIN1148 to RIG-I to drive expression of IFN regulatory factor 3 and NF-κB target genes, including specific immunomodulatory cytokines and chemokines. Intriguingly, KIN1148 does not lead to ATPase activity or compete with ATP for binding but activates RIG-I to induce antiviral gene expression programs distinct from type I IFN treatment. When administered in combination with a vaccine against IAV, KIN1148 induces both neutralizing Ab and IAV-specific T cell responses compared with vaccination alone, which induces comparatively poor responses. This robust KIN1148-adjuvanted immune response protects mice from lethal A/California/04/2009 and H5N1 IAV challenge. Importantly, KIN1148 also augments human CD8+ T cell activation. Thus, we have identified a small molecule RIG-I agonist that serves as an effective adjuvant in inducing noncanonical RIG-I activation for induction of innate immune programs that enhance adaptive immune protection of antiviral vaccination.