Figure 6. Proposed model of type I and type III IFN induction and action in islets from donors carrying the TT and TC rs1990760 genotypes.

CVB3 infection of islets from donors carrying the rs1990760 TT genotype (MDA5, 946 T) (upper model) results in replication of viral RNA and the generation of a viral intermediate (dsRNA). MDA5 binds dsRNA and activates mitochondrial and peroxisomal associated MAVS. This initiates a signalling cascade leading to the phosphorylation and dimerization of IRF-3 through TBK-IKKε, and the degradation of IκB from the NF-κB complex through TRAF6 and TAK1. The activated transcription factors IRF-3 and NF-κB translocate to the nucleus where they bind to the promoter regions of type I and type III IFNs and initiate their expression. In addition, peroxisome associated MAVS leads through unknown mechanisms to the activation of the transcription factor IRF-1, which binds solely to the promoter regions of type III IFNs and selectively initiate their expression. Expressed and secreted type I and type III IFNs bind in an auto- and paracrine manner to their receptors IFNAR and IFNλR, respectively. This in turn activates JAK-TYK2 kinases leading to the formation of the ISGF3 complex and the expression of a large number of ISGs. Infection of islets from donors carrying the rs1990760 TC genotype (MDA5, 946 T/A) (lower model) results in stronger type III IFN gene expression compared to that induced in islets from TT donors, possibly through the peroxisome associated MAVS mediated activation of IRF-1. The stronger type III IFN expression is accompanied by a more robust ISG expression in TC donors compared to TT donors. This includes the expression of IRF-1, which may further amplify the type III IFN expression through a positive feedback mechanism. Why MDA5 activation in donors carrying the rs1990760 TC genotype leads to a stronger activation of peroxisome associated MAVS compared to mitochondrial associated MAVS is still to be discovered.