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RISS 인기검색어
- 검색키워드
- 저자 : Sagartz, John E. (검색결과 1 건)
- 무료
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Toth, Karoly,Lee, Sang R.,Ying, Baoling,Spencer, Jacqueline F.,Tollefson, Ann E.,Sagartz, John E.,Kong, Il-Keun,Wang, Zhongde,Wold, William S. M. Public Library of Science 2015 PLoS pathogens Vol.11 No.8
<▼1><P>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 <I>in vivo</I> 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.</P></▼1><▼2><P><B>Author Summary</B></P><P>The biology of human adenoviruses has been studied extensively; however, much less is known about the replication and pathogenesis of the virus in a permissive host. Our laboratory pioneered the use of Syrian hamsters to study the pathogenesis of human adenoviruses. Syrian hamsters are permissive for species C human adenoviruses, which replicate in these animals and cause illness akin to that in humans. Hereby, we report findings with a new Syrian hamster strain (STAT2 KO hamsters), in which the Type I interferon pathway, an important part of the innate immune response to virus infection, is disrupted. This is the first genetically modified Syrian hamster strain ever reported. We show that these animals are very sensitive to infection with type 5 human adenovirus (Ad5). Ad5 replicates to 100- to 1000-fold higher titers in STAT2 KO hamsters than in wild-type ones, and this increased infection causes enhanced pathology. However, the adaptive immune response to the virus infection seems to be intact with the STAT2 KO hamsters, and surviving animals clear the virus effectively. The data reported here may be of interest to researchers focusing on adenoviruses, and also to those who utilize the Syrian hamster as their animal model for other purposes.</P></▼2>
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