title: Kilham Rat Virus-induced type 1 diabetes involves beta cell infection and intra-islet JAK-STAT activation prior to insulitis.
abstract: We used the LEW1.WR1 rat model of Kilham Rat Virus (KRV)-induced type 1 diabetes (T1D) to test the hypothesis that disease mechanisms are linked with beta cell infection and intra-islet immune activation prior to insulitis. KRV induces genes involved in type I and type II interferon pathways in islet cell lines in vitro and in islets from day-5-infected animals in vivo via mechanisms that do not involve insulitis, beta cell apoptosis, or impaired insulin expression. Immunohistochemistry studies indicated that KRV protein is expressed in beta cells 5 days following infection. KRV induces the phosphorylation of Janus Kinase 1/2 (JAK1/2) and signal transducer and activator of transcription 1 (STAT-1) in islet cells via a mechanism that could involve TLR9 and NF-κB pathways. These data demonstrate for the first time that KRV-induced islet destruction is associated with beta cell infection and intra-islet innate immune upregulation early in the disease process.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Ct., Mail Stop B-140, Aurora, CO 80045, United States.
authors.forename: Aimon K
authors.initials: AK
authors.lastname: Alkanani
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Ct., Mail Stop B-140, Aurora, CO 80045, United States.
authors.forename: Naoko
authors.initials: N
authors.lastname: Hara
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Ct., Mail Stop B-140, Aurora, CO 80045, United States.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gianani
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Ct., Mail Stop B-140, Aurora, CO 80045, United States. Electronic address: danny.zipris@ucdenver.edu.
authors.forename: Danny
authors.initials: D
authors.lastname: Zipris
mesh_terms: D000818:Animals; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000821:virology*; D007249:Inflammation / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology* / Q000821:virology; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D017992:Parvovirus / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms
chemical_list: D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; C507906:Jak1 protein, rat; C507927:Jak2 protein, rat; D053613:Janus Kinase 1; D053614:Janus Kinase 2
keywords: Innate immunity; Islets; Janus kinase; Kilham rat virus; LEW1.WR1 rat; Signal transducer and activator of transcription; Type 1 diabetes