title: Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma.
abstract: Scleroderma (SSc) is a complex and heterogeneous connective tissue disease mainly characterized by autoimmunity, vascular damage, and fibrosis that mostly involve the skin and lungs. Epstein-Barr virus (EBV) is a lymphotropic γ-herpesvirus that has co-evolved with human species, infecting >95% of the adult population worldwide, and has been a leading candidate in triggering several autoimmune diseases. Here we show that EBV establishes infection in the majority of fibroblasts and endothelial cells in the skin of SSc patients, characterized by the expression of the EBV noncoding small RNAs (EBERs) and the increased expression of immediate-early lytic and latency mRNAs and proteins. We report that EBV is able to persistently infect human SSc fibroblasts in vitro, inducing an aberrant innate immune response in infected cells. EBV-Toll-like receptor (TLR) aberrant activation induces the expression of selected IFN-regulatory factors (IRFs), IFN-stimulated genes (ISGs), transforming growth factor-β1 (TGFβ1), and several markers of fibroblast activation, such as smooth muscle actin and Endothelin-1, and all of these genes play a key role in determining the profibrotic phenotype in SSc fibroblasts. These findings imply that EBV infection occurring in mesenchymal, endothelial, and immune cells of SSc patients may underlie the main pathological features of SSc including autoimmunity, vasculopathy, and fibrosis, and provide a unified disease mechanism represented by EBV reactivation.
authors.affiliation: Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA; Institute Pasteur-Fondazione Cenci Bolognetti, Department of Experimental Medicine, University of Rome Sapienza, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Farina
authors.affiliation: Institute Pasteur-Fondazione Cenci Bolognetti, Department of Experimental Medicine, University of Rome Sapienza, Rome, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Cirone
authors.affiliation: Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: York
authors.affiliation: Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Lenna
authors.affiliation: Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Padilla
authors.affiliation: Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mclaughlin
authors.affiliation: Institute Pasteur-Fondazione Cenci Bolognetti, Department of Experimental Medicine, University of Rome Sapienza, Rome, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Faggioni
authors.affiliation: Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.affiliation: Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Trojanowska
authors.affiliation: Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Giuseppina A
authors.initials: GA
authors.lastname: Farina
mesh_terms: D000199:Actins / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D017403:In Situ Hybridization; D007249:Inflammation; D050835:Interferon Regulatory Factors / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D009130:Muscle, Smooth / Q000378:metabolism; D058628:Myofibroblasts / Q000821:virology*; D010641:Phenotype; D058727:RNA, Small Untranslated / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000378:metabolism / Q000821:virology*; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000199:Actins; D019332:Endothelin-1; D050835:Interferon Regulatory Factors; D058727:RNA, Small Untranslated; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D053773:Transforming Growth Factor beta1