title: Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection.
abstract: Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States.
authors.forename: Donna A
authors.initials: DA
authors.lastname: MacDuff
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Reese
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, United States.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Kimmey
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, United States.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Weiss
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States.
authors.forename: Christina
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States.
authors.forename: Amal
authors.initials: A
authors.lastname: Kambal
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States.
authors.forename: Erning
authors.initials: E
authors.lastname: Duan
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Carrero
authors.affiliation: Howard Hughes Medical Institute, New York, United States.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.affiliation: Laboratory of Molecular Signaling and Cell Activation, Institut Pasteur, Centre National de la Recherche Scientifique, Unité de Recherche Associée, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Laplantine
authors.affiliation: Laboratory of Molecular Signaling and Cell Activation, Institut Pasteur, Centre National de la Recherche Scientifique, Unité de Recherche Associée, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Israel
authors.affiliation: St Giles Laboratory of Human Genetics of Infectious Disease, Rockefeller University, New York, United States.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Edelson
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, United States.
authors.forename: L David
authors.initials: LD
authors.lastname: Sibley
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, United States.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Stallings
authors.affiliation: Howard Hughes Medical Institute, New York, United States.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D020170:Caspase 1 / Q000378:metabolism; D002451:Cell Compartmentation; D002908:Chronic Disease; D002954:Citrobacter / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D005816:Genetic Complementation Test; D006564:Herpesviridae / Q000502:physiology*; D006566:Herpesviridae Infections / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000821:virology*; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008089:Listeria monocytogenes / Q000502:physiology; D008088:Listeriosis / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000502:physiology; D010641:Phenotype; D018144:Rhadinovirus / Q000502:physiology; D014122:Toxoplasma; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D044767:Ubiquitin-Protein Ligases; D020170:Caspase 1
keywords: Listeria monocytogenes; NF-kappaB; immunodeficiency; immunology; infectious disease; linear ubiquitination; microbiology; mouse; murine gamma-herpesvirus 68