title: Immune-Complexed Adenovirus Induce AIM2-Mediated Pyroptosis in Human Dendritic Cells.
abstract: Human adenoviruses (HAdVs) are nonenveloped proteinaceous particles containing a linear double-stranded DNA genome. HAdVs cause a spectrum of pathologies in all populations regardless of health standards. Following repeat exposure to multiple HAdV types, we develop robust and long-lived humoral and cellular immune responses that provide life-long protection from de novo infections and persistent HAdV. How HAdVs, anti-HAdV antibodies and antigen presenting cells (APCs) interact to influence infection is still incompletely understood. In our study, we used physical, pharmacological, biochemical, fluorescence and electron microscopy, molecular and cell biology approaches to dissect the impact of immune-complexed HAdV (IC-HAdV) on human monocyte-derived dendritic cells (MoDCs). We show that IC-HAdV generate stabilized complexes of ~200 nm that are efficiently internalized by, and aggregate in, MoDCs. By comparing IC-HAdV, IC-empty capsid, IC-Ad2ts1 (a HAdV-C2 impaired in endosomal escape due to a mutation that impacts protease encapsidation) and IC-AdL40Q (a HAdV-C5 impaired in endosomal escape due to a mutation in protein VI), we demonstrate that protein VI-dependent endosomal escape is required for the HAdV genome to engage the DNA pattern recognition receptor AIM2 (absent in melanoma 2). AIM2 engagement induces pyroptotic MoDC death via ASC (apoptosis-associated speck protein containing a caspase activation/recruitment domain) aggregation, inflammasome formation, caspase 1 activation, and IL-1β and gasdermin D (GSDMD) cleavage. Our study provides mechanistic insight into how humoral immunity initiates an innate immune response to HAdV-C5 in human professional APCs.
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS 5535, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Karsten
authors.initials: K
authors.lastname: Eichholz
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS 5535, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Bru
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS 5535, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Thi Thu Phuong
authors.initials: TT
authors.lastname: Tran
authors.affiliation: iBET- Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.|Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Fernandes
authors.affiliation: Division of Immunology and Allergy, University of Lausanne, Lausanne, Switzerland.
authors.forename: Hugh
authors.identifier: 0000-0002-3336-1203
authors.initials: H
authors.lastname: Welles
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS 5535, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Franck J D
authors.initials: FJ
authors.lastname: Mennechet
authors.affiliation: Institut Curie, INSERM U932, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Manel
authors.affiliation: iBET- Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.|Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Alves
authors.affiliation: Division of Immunology and Allergy, University of Lausanne, Lausanne, Switzerland.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Perreau
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS 5535, Montpellier, France.|Université de Montpellier, Montpellier, France.
authors.forename: Eric J
authors.identifier: 0000-0001-6114-7530
authors.initials: EJ
authors.lastname: Kremer
mesh_terms: D000257:Adenoviridae Infections / Q000276:immunology* / Q000821:virology; D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000276:immunology*; D020170:Caspase 1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology; D053583:Interleukin-1beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D000069292:Pyroptosis / Q000276:immunology*; D000094524:Gasdermins
chemical_list: D000936:Antigen-Antibody Complex; D020170:Caspase 1; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D028044:Phosphate-Binding Proteins; C410167:AIM2 protein, human; C498366:GSDMD protein, human; D000094524:Gasdermins