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.
Highlights
Human adenoviruses (Ads) are non-enveloped, double-stranded DNA viruses that are classified into over 60 types (Ad1, Ad2, etc.), which in turn are grouped into 7 species (A to G)
The biology of human adenoviruses has been studied extensively; much less is known about the replication and pathogenesis of the virus in a permissive host
Syrian hamsters are permissive for species C human adenoviruses, which replicate in these animals and cause illness akin to that in humans
Summary
Human adenoviruses (Ads) are non-enveloped, double-stranded DNA viruses that are classified into over 60 types (Ad1, Ad2, etc.), which in turn are grouped into 7 species (A to G) (for a review on Ad biology, see [1, 2]). Ads cause a variety of diseases in humans; the symptoms range from respiratory to enteric, ocular and urinary, depending on the type of Ad. Generally, in immunocompetent adults the course of the infections is mild, and it resolves without the need for medical intervention (for a review of Ad epidemiology and pathology, see [3, 5]). Infection with a specific type causes long-term immunity to that type. The most extreme case of the host’s influence on the illness caused by Ads is seen with immunocompromised patients. For these patients, the same types that cause self-resolving illness in healthy adults can cause serious, often life-threatening illness. In allogeneic hematopoietic stem cell transplant patients with a rising load of Ad in peripheral blood (as determined by quantitative PCR [qPCR]) despite antiviral therapy, the mortality can approach 100% [3, 6, 7]
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