title: Activation of innate immune defense mechanisms contributes to polyomavirus BK-associated nephropathy.
abstract: Polyomavirus-associated nephropathy (PVAN) is a significant complication after kidney transplantation, often leading to premature graft loss. In order to identify antiviral responses of the renal tubular epithelium, we studied activation of the viral DNA and the double-stranded RNA (dsRNA) sensors Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I) in allograft biopsy samples of patients with PVAN, and in human collecting duct cells in culture after stimulation by the dsRNA mimic polyriboinosinic:polyribocytidylic acid (poly(I:C)), cytokines, or infection with BK virus. Double staining using immunofluorescence for BK virus and TLR3 showed strong signals in epithelial cells of distal cortical tubules and the collecting duct. In biopsies microdissected to isolate tubulointerstitial lesions, TLR3 but not RIG-I mRNA expression was found to be increased in PVAN. Collecting duct cells in culture expressed TLR3 intracellularly, and activation of TLR3 and RIG-I by poly(I:C) enhanced expression of cytokine, chemokine, and IFN-β mRNA. This inflammatory response could be specifically blocked by siRNA to TLR3. Finally, infection of the collecting duct cells with BK virus enhanced the expression of cytokines and chemokines. This led to an efficient antiviral immune response with TLR3 and RIG-I upregulation without activation of IL-1β or components of the inflammasome pathway. Thus, PVAN activation of innate immune defense mechanisms through TLR3 is involved in the antiviral and anti-inflammatory response leading to the expression of proinflammatory cytokines and chemokines.
authors.affiliation: Medizinische Poliklinik Campus Innenstadt, Klinikum der LMU, Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Markus
authors.initials: M
authors.lastname: Wörnle
authors.forename: Nasim
authors.initials: N
authors.lastname: Motamedi
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Anders
authors.forename: Elisabeth F
authors.initials: EF
authors.lastname: Gröne
authors.forename: Hans
authors.initials: H
authors.lastname: Nitschko
authors.forename: Peter
authors.initials: P
authors.lastname: Kurktschiev
authors.forename: Hanna
authors.initials: H
authors.lastname: Debiec
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: Hermann J
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
authors.forename: Holger
authors.initials: H
authors.lastname: Schmid
mesh_terms: D001739:BK Virus / Q000276:immunology / Q000472:pathogenicity; D001483:Base Sequence; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D007113:Immunity, Innate; D007674:Kidney Diseases / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D027601:Polyomavirus Infections / Q000150:complications / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011971:Receptors, Immunologic; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D014412:Tumor Virus Infections / Q000150:complications / Q000235:genetics / Q000276:immunology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases