Viral double-stranded RNA sensors induce antiviral, pro-inflammatory, and pro-apoptotic responses in human renal tubular epithelial cells.
Viral infection in the kidney is characterized by tubular injury induced directly by the virus and/or by cytotoxic lymphocytes. Previously, we found that human tubular epithelial cells express Toll-like receptor 3 (TLR3), melanoma differentiation-associated gene 5 (MDA5), and retinoic acid-inducible gene-I (RIG-I), all sensors of double-stranded RNA (dsRNA) and potent inducers of antiviral activity. Here, we demonstrate increased expression of these three dsRNA sensors in kidney transplant biopsies during cytomegalovirus or BK virus infection. In primary tubular epithelial cells, dsRNA sensor activation induced the production of pro-inflammatory TNF-α and antiviral IFN-β. Notably, dsRNA also enhanced the expression of pro-apoptotic proteins; however, dsRNA alone did not cause cell death due to the expression of anti-apoptotic proteins. The dsRNA sensitized tubular epithelial cells to apoptosis induced by an agonistic antibody against the Fas receptor (CD95), an apoptotic pathway that eliminates infected cells. These findings indicate that tubular epithelial cells require at least two signals to undergo apoptosis, which can help preserve tubular integrity even under inflammatory conditions. Thus, sensors of viral dsRNA promote antiviral, pro-inflammatory, and pro-apoptotic responses in tubular epithelial cells, which may orchestrate the control of viral infection in the kidney.
Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands. K.M.Heutinck@amc.uva.nl
Kirstin M
KM
Heutinck
Ajda T
AT
Rowshani
Jorien
J
Kassies
Nike
N
Claessen
Karlijn A M I
KA
van Donselaar-van der Pant
Fréderike J
FJ
Bemelman
Eric
E
Eldering
René A W
RA
van Lier
Sandrine
S
Florquin
Ineke J M
IJ
Ten Berge
Jörg
J
Hamann
D000328:Adult; D000368:Aged; D017209:Apoptosis; D001739:BK Virus / Q000235:genetics*; D001706:Biopsy; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D005260:Female; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D018836:Inflammation Mediators / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D027601:Polyomavirus Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000821:virology; D012330:RNA, Double-Stranded / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism*; D011971:Receptors, Immunologic; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D019014:fas Receptor / Q000378:metabolism
C491901:FAS protein, human; D018836:Inflammation Mediators; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D011971:Receptors, Immunologic; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D016899:Interferon-beta; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1