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

Toth K, Lee SR, Ying B, Spencer JF, Tollefson AE, Sagartz JE, Kong IK, Wang Z, Wold WS - PLoS Pathog. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

STAT2 KO hamsters fail to up-regulate the expression of interferon-stimulated genes PKR (A, D), OAS (B, E), and Mx2 (C, F) in the liver (A-C) and spleen (D-F).Fold changes in mRNA levels are shown; symbols denote data from individual animals; empty symbols signify that the samples were collected from an animal that was sacrificed moribund. *: P<0.05; **: P<0.01; ***: P<0.001.
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ppat.1005084.g004: STAT2 KO hamsters fail to up-regulate the expression of interferon-stimulated genes PKR (A, D), OAS (B, E), and Mx2 (C, F) in the liver (A-C) and spleen (D-F).Fold changes in mRNA levels are shown; symbols denote data from individual animals; empty symbols signify that the samples were collected from an animal that was sacrificed moribund. *: P<0.05; **: P<0.01; ***: P<0.001.

Mentions: If the Type I IFN response is impaired in the STAT2 KO hamsters, then we would expect that transcription of IFN-stimulated genes (ISGs) would be impaired. RT-qPCR was utilized to detect changes in the expression levels of ISGs in the liver, namely protein kinase R (double-stranded RNA-dependent protein kinase, PKR), oligoadenylate synthetase (OAS), and IFN-induced GTP-binding protein (Mx2). Baseline levels of PKR and Mx2 were significantly elevated in the livers of wt hamsters compared to the STAT2 KO animals (Fig 4A and 4C). The difference was much more striking after Ad5 infection: for the wt hamsters’ transcripts, all three ISGs assayed were extremely elevated at 1 and 3 days post challenge, while no such elevation was observed for the STAT2 KO animals (Fig 4A–4C). The induction of ISGs was similarly impeded in the spleen (Fig 4D–4F).


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

Toth K, Lee SR, Ying B, Spencer JF, Tollefson AE, Sagartz JE, Kong IK, Wang Z, Wold WS - PLoS Pathog. (2015)

STAT2 KO hamsters fail to up-regulate the expression of interferon-stimulated genes PKR (A, D), OAS (B, E), and Mx2 (C, F) in the liver (A-C) and spleen (D-F).Fold changes in mRNA levels are shown; symbols denote data from individual animals; empty symbols signify that the samples were collected from an animal that was sacrificed moribund. *: P<0.05; **: P<0.01; ***: P<0.001.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4546297&req=5

ppat.1005084.g004: STAT2 KO hamsters fail to up-regulate the expression of interferon-stimulated genes PKR (A, D), OAS (B, E), and Mx2 (C, F) in the liver (A-C) and spleen (D-F).Fold changes in mRNA levels are shown; symbols denote data from individual animals; empty symbols signify that the samples were collected from an animal that was sacrificed moribund. *: P<0.05; **: P<0.01; ***: P<0.001.
Mentions: If the Type I IFN response is impaired in the STAT2 KO hamsters, then we would expect that transcription of IFN-stimulated genes (ISGs) would be impaired. RT-qPCR was utilized to detect changes in the expression levels of ISGs in the liver, namely protein kinase R (double-stranded RNA-dependent protein kinase, PKR), oligoadenylate synthetase (OAS), and IFN-induced GTP-binding protein (Mx2). Baseline levels of PKR and Mx2 were significantly elevated in the livers of wt hamsters compared to the STAT2 KO animals (Fig 4A and 4C). The difference was much more striking after Ad5 infection: for the wt hamsters’ transcripts, all three ISGs assayed were extremely elevated at 1 and 3 days post challenge, while no such elevation was observed for the STAT2 KO animals (Fig 4A–4C). The induction of ISGs was similarly impeded in the spleen (Fig 4D–4F).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus