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.
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
Karoly
K
Toth
Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, United States of America.
Sang R
SR
Lee
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
Baoling
B
Ying
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
Jacqueline F
JF
Spencer
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
Ann E
AE
Tollefson
Department of Comparative Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
John E
JE
Sagartz
Department of Animal Science, Division of Applied Life Science and Institute of Agriculture and Life Science, Gyeongsang National University, Jinju, Republic of Korea.
Il-Keun
IK
Kong
Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, United States of America.
Zhongde
Z
Wang
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.
William S M
WS
Wold
D000257:Adenoviridae Infections / Q000276:immunology* / Q000473:pathology; D000260:Adenoviruses, Human / Q000276:immunology / Q000472:pathogenicity*; D000818:Animals; D030801:Animals, Genetically Modified; D045744:Cell Line, Tumor; D006224:Cricetinae; D004195:Disease Models, Animal; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D008647:Mesocricetus; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050795:STAT2 Transcription Factor / Q000172:deficiency* / Q000276:immunology
D007370:Interferon Type I; D050795:STAT2 Transcription Factor