STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus,Revealing an Important Role of Type I Interferon Response in Viral Control

Human adenoviruses have been studied extensively in cell culture and have been a model for studies in molecular,cellular,and medical biology. however,much less is known about adenovirus replication and pathogenesis in vivo in a permissive host because of the lack of an adequate animal model. presently,the most frequently used permissive immunocompetent animal model for human adenovirus infection is the syrian hamster. species c human adenoviruses replicate in these animals and cause pathology that is similar to that seen with humans. here,we report findings with a new syrian hamster strain in which the stat2 gene was functionally knocked out by site-specific gene targeting. adenovirus-infected stat2 knockout hamsters demonstrated an accentuated pathology compared to the wild-type control animals,and the virus load in the organs of stat2 knockout animals was 100- to 1000-fold higher than that in wild-type hamsters. notably,the adaptive immune response to adenovirus is not adversely affected in stat2 knockout hamsters,and surviving hamsters cleared the infection by 7 to 10 days post challenge. we show that the type i interferon pathway is disrupted in these hamsters,revealing the critical role of interferon-stimulated genes in controlling adenovirus infection. this is the first study to report findings with a genetically modified syrian hamster infected with a virus. further,this is the first study to show that the type i interferon pathway plays a role in inhibiting human adenovirus replication in a permissive animal model. besides providing an insight into adenovirus infection in humans,our results are also interesting from the perspective of the animal model: stat2 knockout syrian hamster may also be an important animal model for studying other viral infections,including ebola-,hanta-,and dengue viruses,where type i interferon-mediated innate immunity prevents wild type hamsters from being effectively infected to be used as animal models. © 2015 toth et al.