Kilham rat virus-induced type 1 diabetes involves beta cell infection and intra-islet JAK-STAT activation prior to insulitis

•KRV induces proinflammatory gene expression in islets shortly after virus inoculation•KRV infects islet cell lines in vitro and beta cells in vivo•Insulitis and T1D are preceded by beta cell infection and intra-islet innate immune activation

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.