Hypothesis: Fulminant Type 1 diabetes is a unique subtype of T1D, mostly reported in the Japanese population, which is characterized by extensive beta cell death already at onset, often without any insulitis. Enterovirus (EV) infections are associated with the etiology of both fulminant and conventional T1D. However the causative mechanism is not known for any of these diseases. EVs capability to cause lytic vs non-lytic infection in explanted human islets may have implications on the pathogenesis of these two types of T1D.
Aim: To study the effect of infection of explanted human pancreatic islets with lytic (CBV-1) and non-lytic (CBV-4) Coxsackie B virus strains on cytopathic effect/islet disintegration and to what extent genes involved in viral sensing, antiviral defense and encoding of islet auto-antigens are affected by the viral replication. Also, to compare these findings with the findings reported in fulminant and conventional T1D.
Methods: Degree of cytopathic effect/islet disintegration was studied and viral replication was measured. Genes involved in viral sensing (NOD2, TLR7 and TLR4), antiviral pathways (OAS2, MX1, PKR, and IRF7), genes coding for known islet auto antigens (GAD65, ZNT8) and the islet hormones, insulin and glucagon, were studied. Mock-infected explanted islet served as controls.
Results: All CBV strains replicated in the explanted islets but only the CBV-1 strains caused cytopathic effect/islet cell disintegration. Infection with all CBV strains resulted in the induction of genes encoding OAS2 and MX1. In contrast, mRNA expression levels of the gene encoding insulin was reduced. The gene encoding PKR was induced by one of the lytic strains (CBV-1-11) and also by the non-lytic CBV4 strain, while the mRNA expression levels of genes encoding glucagon, NOD2, TLR7, TLR4, MCL1, GAD65 and ZNT8 were not significantly affected.