title: RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection.
abstract: Coxsackievirus (CV) is an important human pathogen that has been linked to the development of autoimmunity. An intact pancreatic beta cell IFN response is critical for islet cell survival and protection from type 1 diabetes following CV infection. In this study, we show that IFNs trigger an antiviral state in beta cells by inducing the expression of proteins involved in intracellular antiviral defense. Specifically, we demonstrate that 2',5'-oligoadenylate synthetases (2-5AS), RNase L, and dsRNA-dependent protein kinase (PKR) are expressed by pancreatic islet cells and that IFNs (IFN-alpha and IFN-gamma) increase the expression of 2-5AS and PKR, but not RNase L. Moreover, our in vitro studies uncovered that these pathways play important roles in providing unique and complementary antiviral activities that critically regulate the outcome of CV infection. The 2-5AS/RNase L pathway was critical for IFN-alpha-mediated islet cell resistance from CV serotype B4 (CVB4) infection and replication, whereas an intact PKR pathway was required for efficient IFN-gamma-mediated repression of CVB4 infection and replication. Finally, we show that the 2-5AS/RNase L and the PKR pathways play important roles for host survival during a challenge with CVB4. In conclusion, this study has dissected the pathways used by distinct antiviral signals and linked their expression to defense against CVB4.
authors.affiliation: Department of Immunology, IMM-23, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Malin
authors.initials: M
authors.lastname: Flodström-Tullberg
authors.forename: Monica
authors.initials: M
authors.lastname: Hultcrantz
authors.forename: Alexandr
authors.initials: A
authors.lastname: Stotland
authors.forename: Amy
authors.initials: A
authors.lastname: Maday
authors.forename: Devin
authors.initials: D
authors.lastname: Tsai
authors.forename: Cody
authors.initials: C
authors.lastname: Fine
authors.forename: Bryan
authors.initials: B
authors.lastname: Williams
authors.forename: Robert
authors.initials: R
authors.lastname: Silverman
authors.forename: Nora
authors.initials: N
authors.lastname: Sarvetnick
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D029822:Enterovirus B, Human / Q000254:growth & development / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007515:Islets of Langerhans / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology; D019892:eIF-2 Kinase / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007371:Interferon-gamma; D019892:eIF-2 Kinase; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease