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dc.contributor.authorFrieman, M.
dc.contributor.authorYount, B.
dc.contributor.authorPage, C.
dc.date.accessioned2020-03-27T15:13:17Z
dc.date.available2020-03-27T15:13:17Z
dc.date.issued2012
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84856908736&doi=10.1128%2fJVI.05957-11&partnerID=40&md5=b6c7177125d22167d70874b58ddc586f
dc.identifier.urihttp://hdl.handle.net/10713/12424
dc.description.abstractSARS coronavirus (SARS-CoV) causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology often progresses to acute respiratory distress (such as acute respiratory distress syndrome [ARDS]) and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and aged (1-year-old) mice do not develop severe clinical disease following infection with wild-type SARS-CoV, a mouse-adapted strain of SARS-CoV (called MA15) was developed and was shown to cause lethal infection in these animals. To understand the genetic contributions to the increased pathogenesis of MA15 in rodents, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral spike (S) glycoprotein and, to a much less rigorous extent, in the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse angiotensin-converting enzyme 2 (ACE2) receptor not only in MA15 but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to the findings for young animals, mutations to revert to the wild-type sequence in nsp9 and the S glycoprotein were not sufficient to significantly attenuate the virus compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease.en_US
dc.description.urihttps://doi.org/10.1128/JVI.05957-11en_US
dc.language.isoen_USen_US
dc.relation.ispartofJournal of Virology
dc.subjectsevere acute respiratory syndrome coronavirusen_US
dc.subjectSARS-CoVen_US
dc.subjectpathogenesisen_US
dc.subject.meshSARS Virusen_US
dc.subject.meshVirulenceen_US
dc.subject.meshModels, Animalen_US
dc.subject.meshMiceen_US
dc.titleMolecular determinants of severe acute respiratory syndrome coronavirus pathogenesis and virulence in young and aged mouse models of human diseaseen_US
dc.typeArticleen_US
dc.identifier.doi10.1128/JVI.05957-11
dc.identifier.pmid22072787
dc.identifier.ispublishedNo


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