A Critical Role for the Type I Interferon Receptor in Virus-Induced Autoimmune Diabetes in Rats

Abstract

The pathogenesis of human type 1 diabetes, characterized by immune-mediated damage of insulin-producing β-cells of pancreatic islets, may involve viral infection. Essential components of the innate immune antiviral response, including type I interferon (IFN) and IFN receptor–mediated signaling pathways, are candidates for determining susceptibility to human type 1 diabetes. Numerous aspects of human type 1 diabetes pathogenesis are recapitulated in the LEW.1WR1 rat model. Diabetes can be induced in LEW.1WR1 weanling rats challenged with virus or with the viral mimetic polyinosinic:polycytidylic acid (poly I:C). We hypothesized that disrupting the cognate type I IFN receptor (type I IFN α/β receptor [IFNAR]) to interrupt IFN signaling would prevent or delay the development of virus-induced diabetes. We generated IFNAR1 subunit–deficient LEW.1WR1 rats using CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats–associated protein 9) genome editing and confirmed functional disruption of the Ifnar1 gene. IFNAR1 deficiency significantly delayed the onset and frequency of diabetes and greatly reduced the intensity of insulitis after poly I:C treatment. The occurrence of Kilham rat virus–induced diabetes was also diminished in IFNAR1-deficient animals. These findings firmly establish that alterations in innate immunity influence the course of autoimmune diabetes and support the use of targeted strategies to limit or prevent the development of type 1 diabetes.

Innate Viral Receptor Signaling Determines Type 1 Diabetes Onset

“…Islets from patients recently experiencing onset of T1D exhibit heightened expression of certain ISGs in the islet and peri-islet regions in a manner which is similar to islets infected with virus ( 72 ). Knocking out the type I IFN receptor (IFNAR) in the T1D-susceptible rat strain, LEW.1WR1, protects from T1D, reduces insulitis, and delays onset following poly I:C or virus challenge ( 73 ). Originating with PRR stimulation, aberrant activation of pDCs and genetic mutations in the IFN signaling pathway likely contribute to the IFN signature evident in T1D induction ( 74 ).…”

Type 1 Interferons Potentiate Human CD8+ T-Cell Cytotoxicity Through a STAT4- and Granzyme B–Dependent Pathway

“…Although knockout of the IFNα receptor (IFNAR) in NOD mice has produced results to the contrary, a preponderance of evidence in preclinical models also supports a pathogenic role for T1-IFN in T1D ( 15 – 18 ). For example, CRISPR-Cas9 deletion of the IFNAR1 subunit in LEW.1WR1 rats delays spontaneous and polyinosinic-polycytidylic acid–induced diabetes ( 17 ). Additionally, studies revealed that overexpression of IFNα in pancreatic β-cells of nondiabetes-prone mice regulates the onset of diabetes in mice with severe insulitis, whereas expression of IFNβ in islets of NOD mice accelerated autoimmunity ( 19 – 21 ).…”

Genetic Susceptibility of the Host in Virus-Induced Diabetes

“…These rats also showed a reduced incidence of poly(I:C)-induced autoimmune diabetes. The splenic cells from the Ifnar1-deficient rats with KRV showed reduced expression of C-X-C motif chemokine ligand (Cxcl) 10 and C-C motif chemokine ligand (Ccl) 5, whereas the expression of Il-1β and Ccl2 was increased [103]. These findings indicate that type 1 IFN-mediated signaling is associated with the development of autoimmune diabetes induced by KRV [103].…”

“…In IFN-α receptor 1 (Ifnar1)-deficient LEW.1WR1 rats, the incidence of KRV-induced diabetes was shown to be reduced [103]. These rats also showed a reduced incidence of poly(I:C)-induced autoimmune diabetes.…”