๐ Synthetic reconstruction of zoonotic and early human severe acute respiratory syndrome coronavirus isolates that produce fatal disease in aged mice
The severe acute respiratory syndrome (SARS) epidemic was characterized by high mortality rates in the elderly. The molecular mechanisms that govern enhanced susceptibility of elderly populations are not known, and robust animal models are needed that recapitulate the increased pathogenic phenotype noted with increasing age. Using synthetic biology and reverse genetics, we describe the construction of a panel of isogenic SARS coronavirus (SARS-CoV) strains bearing variant spike glycoproteins that are representative of zoonotic strains found in palm civets and raccoon dogs, as well as isolates spanning the early, middle, and late phases of the SARS-CoV epidemic. The recombinant viruses replicated efficiently in cell culture and demonstrated variable sensitivities to neutralization with antibodies. The human but not the zoonotic variants replicated efficiently in human airway epithelial cultures, supporting earlier hypotheses that zoonotic isolates are less pathogenic in humans but can evolve into highly pathogenic strains. All viruses replicated efficiently, but none produced clinical disease or death in young animals. In contrast, severe clinical disease, diffuse alveolar damage, hyaline membrane formation, alveolitis, and death were noted in 12-month-old mice inoculated with the palm civet HC/SZ/61/03 strain or early-human-phase GZ02 variants but not with related middle- and late-phase epidemic or raccoon dog strains. This panel of SARS-CoV recombinants bearing zoonotic and human epidemic spike glycoproteins will provide heterologous challenge models for testing vaccine efficacy against zoonotic reintroductions as well as provide the appropriate model system for elucidating the complex virus-host interactions that contribute to more-severe and fatal SARS-CoV disease and acute respiratory distress in the elderly. Copyright ยฉ 2007, American Society for Microbiology.
keywords
๐ severe acute (1373)
๐ recombinant viruses (43)
๐ highly pathogenic (100)
๐ reverse genetics (49)
๐ high mortality (78)
๐ animal models (72)
๐ palm civets (20)
๐ spike glycoprotein (99)
๐ respiratory syndrome (2004)
๐ respiratory distress (139)
๐ acute respiratory (1734)
๐ cell culture (240)
๐ diffuse alveolar (21)
author
๐ค Rockx, Barry
๐ค Sheahan, Timothy
๐ค Donaldson, Eric
๐ค Harkema, Jack
๐ค Sims, Amy
๐ค Heise, Mark
๐ค Pickles, Raymond
๐ค Cameron, Mark
๐ค Kelvin, David
๐ค Baric, Ralph
year
โฐ 2007
journal
๐ Journal of Virology
issn
๐ 0022538X
volume
81
number
14
page
7410-7423
citedbycount
46
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