ADAR1 haploinsufficiency and sustained viral RdRp dsRNA synthesis synergize to dysregulate RNA editing and cause multi-system interferonopathy

Sensing of viral double-stranded RNA by MDA5 triggers abundant but transient expression of interferon-stimulated genes (ISGs). If dsRNA synthesis is made persistent by transgenic expression of a picornaviral RNA-dependent RNA polymerase (RdRp) in mice, lifelong MDA5-MAVS pathway activation and marked, global ISG upregulation results. This confers robust protection from diverse viral diseases but in contrast to numerous other chronic MDA5 hyperactivation states, the mice do not suffer autoimmune or autoinflammatory consequences. However, knockout of one allele of Adar, which by itself is also well-tolerated, breaks the protective state and results in a severe disease that resembles interferonopathies caused by MDA5 gain-of-function (GOF) mutations. Gene expression profiles of whole brain total RNA from WT and hemizyogous RdRp mice with or without knockout of one Adar1 allele were compared, and used in conjunction with whole-genome sequencing of the same animals to examine changes in A-to-I editing.