title: Activation of the NLRP3 inflammasome by vault nanoparticles expressing a chlamydial epitope.
abstract: The full potential of vaccines relies on development of effective delivery systems and adjuvants and is critical for development of successful vaccine candidates. We have shown that recombinant vaults engineered to encapsulate microbial epitopes are highly stable structures and are an ideal vaccine vehicle for epitope delivery which does not require the inclusion of an adjuvant. We studied the ability of vaults which were engineered for use as a vaccine containing an immunogenic epitope of Chlamydia trachomatis, polymorphic membrane protein G (PmpG), to be internalized into human monocytes and behave as a "natural adjuvant". We here show that incubation of monocytes with the PmpG-1-vaults activates caspase-1 and stimulates IL-1β secretion through a process requiring the NLRP3 inflammasome and that cathepsin B and Syk are involved in the inflammasome activation. We also observed that the PmpG-1-vaults are internalized through a pathway that is transiently acidic and leads to destabilization of lysosomes. In addition, immunization of mice with PmpG-1-vaults induced PmpG-1 responsive CD4(+) cells upon re-stimulation with PmpG peptide in vitro, suggesting that vault vaccines can be engineered for specific adaptive immune responses. We conclude that PmpG-1-vault vaccines can stimulate NLRP3 inflammasomes and induce PmpG-specific T cell responses.
authors.affiliation: Department of Molecular Cell Biology, and Health Sciences Research Institute, University of California, Merced, CA 95343, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Janina
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Molecular Cell Biology, and Health Sciences Research Institute, University of California, Merced, CA 95343, USA.
authors.forename: Najwane
authors.initials: N
authors.lastname: Said-Sadier
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Gale
authors.initials: G
authors.lastname: Boxx
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Champion
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Tetlow
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Kickhoefer
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Rome
authors.affiliation: Department of Molecular Cell Biology, and Health Sciences Research Institute, University of California, Merced, CA 95343, USA. Electronic address: david.ojcius@gmail.com.
authors.forename: David M
authors.initials: DM
authors.lastname: Ojcius
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: KKelly@mednet.ucla.edu.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Kelly
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology*; D001428:Bacterial Vaccines / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology*; D020170:Caspase 1 / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D002692:Chlamydia trachomatis / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053758:Nanoparticles; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D000072377:Syk Kinase
chemical_list: D000276:Adjuvants, Immunologic; D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D002352:Carrier Proteins; D000939:Epitopes; D058847:Inflammasomes; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C410161:PmpG protein, Chlamydia trachomatis; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D002401:Cathepsin B; D020170:Caspase 1
keywords: Chlamydia; Inflammasomes; Lysosomes; Vaults