Danica Sutherland, University of Pittsburgh

Danica M. Sutherland,1,2* Xinfeng Guo,3* Qingde Wang,3,4,5 and Terence S. Demody1,2,6 1 Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 2 Institute of Infection, Inflammation, and Immunity, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 3 Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 4 Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA 5 Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 6 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, USA

Pathogenesis and Immunity

Viral infections can initiate or antagonize autoinflammatory disorders. However, mechanisms underlying virus-induced immune dysregulation are often unclear. Aicardi-Goutières Syndrome (AGS) is a rare genetic disorder characterized by systemic upregulation of type 1 interferons, microcalcifications in the brain, and neurologic decline. Some cases of AGS are attributable to mutations in the adenosine deaminase acting on RNA 1 (ADAR1) protein, which modifies host and viral dsRNA to render it less inflammatory. Mice expressing a human K999N polymorphism in ADAR1 have a robust interferonopathy but lack other hallmarks of AGS. To determine whether viral infection contributes to AGS-like findings in mice, we inoculated newborn ADAR1 heterozygous or homozygous mutant mice with a replication-impaired strain of mammalian orthoreovirus (reovirus) and monitored for disease phenotypes. All infected Adar1-homozygous-deficient mice succumbed to infection, whereas heterozygous littermates survived, although the trajectory of weight gain was diminished compared with mock-inoculated animals. While immunohistochemical analyses of infected brain tissue revealed some evidence of calcium deposition, no genotype-specific patterns were evident. Both genotypes had incomplete penetrance of severe manifestations of reovirus infection, including evidence of colitis, myocarditis, and stroke, suggesting a dose-dependent role for Adar1 in viral pathogenesis and virulence. Additionally, reovirus loads in heart and liver tissue were higher in Adar1-homozygous-deficient mice relative to littermate controls. These data suggest an essential role for ADAR1 in antagonizing reovirus virulence and highlight opportunities to further develop mouse models of AGS using environmental triggers such as viral infection.