title: Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59.
abstract: Clinical studies have indicated that subvirion inactivated vaccines against avian influenza viruses, particularly H5N1, are poorly immunogenic in humans. As a consequence, the use of adjuvants has been championed for the efficient vaccination of a naïve population against avian influenza. Aluminum salts (alum) and the oil-in-water emulsion MF59 are safe and effective adjuvants that are being used with influenza vaccines, but the mechanism underlying their stimulation of the immune system remains poorly understood. It was shown recently that activation of a cytosolic innate immune-sensing complex known as "NLR-Pyrin domain containing 3" (NLRP3) inflammasome, also known as "cryopyrin," "cold-induced autoinflammatory syndrome 1" (CIAS1), or nacht domain-, leucine-rich repeat-, and PYD-containing protein 3 (Nalp3), is essential for the adjuvant effect of alum. Here we show that the inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adapter protein within the NLRP3 inflammasome, is a crucial element in the adjuvant effect of MF59 when combined with H5N1 subunit vaccines. In the absence of ASC, H5-specific IgG antibody responses are significantly reduced, whereas the responses are intact in NLRP3(-/-) and caspase-1(-/-) mice. This defect is caused mainly by the failure of antigen-specific B cells to switch from IgM to IgG production. We conclude that ASC plays an inflammasome-independent role in the induction of antigen-specific humoral immunity after vaccination with MF59-adjuvanted influenza vaccines. These findings have important implications for the rational design of next-generation adjuvants.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Ellebedy
authors.forename: Christopher
authors.initials: C
authors.lastname: Lupfer
authors.forename: Hazem E
authors.initials: HE
authors.lastname: Ghoneim
authors.forename: Jennifer
authors.initials: J
authors.lastname: DeBeauchamp
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Webby
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D006386:Hemagglutination Tests; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000627:therapeutic use*; D007251:Influenza, Human / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011136:Polysorbates / Q000627:therapeutic use*; D013185:Squalene / Q000627:therapeutic use*; D018709:Statistics, Nonparametric
chemical_list: D000276:Adjuvants, Immunologic; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D007252:Influenza Vaccines; C089950:MF59 oil emulsion; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D011136:Polysorbates; D013185:Squalene; D020170:Caspase 1