Pathways of Cross Species Transmission of Synthetically Reconstructed Zoonotic SARS-CoV.
June 28th, 2008 | by admin |Pathways of Cross Species Transmission of Synthetically Reconstructed Zoonotic SARS-CoV.
Zoonotic SARS Coronavirus (SARS-CoV) likely evolved to infect humans by a series of transmission events between humans and animals in markets in China. Virus sequence data suggests the palm civet served as an amplification host where civet and human interaction fostered the evolution of the epidemic strain SARS Urbani (Urbani). The prototypic civet strain of SARS-CoV, SZ16, was isolated from a palm civet but has not been successfully cultured in vitro. In order to propagate a chimeric recombinant SARS-CoV bearing an SZ16 Spike (S) glycoprotein, we constructed cell lines expressing the civet ortholog (DBT-cACE2) of the SARS-CoV receptor (hACE2). Zoonotic SARS-CoV was completely dependent on ACE2 for entry. Urbani grew with similar kinetics in both DBT-cACE2 and DBT-hACE2 cells while icSZ16-S only grew within DBT-cACE2 cells. SZ16 S mutant viruses adapted to human airway epithelial cells displayed enhanced affinity for hACE2 but exhibited severe growth defects in DBT-cACE2 cells suggesting the evolutionary pathway that promoted efficient hACE2 interactions, simultaneously abolished efficient cACE2 interactions. Structural modeling predicted two distinct biochemical interaction networks by which zoonotic RBD architectures can productively engage hACE2 but only the Urbani mutational repertoire promoted efficient usage of both hACE2 and cACE2 binding interfaces. Since dual species tropism was preserved in Urbani, it is likely that it evolved a high affinity for cACE2/hACE2 receptors through adaptation via repeated passage between human and civet hosts. Further, zoonotic SARS-CoV was variably neutralized by antibodies that were effective against the epidemic strain highlighting their utility to evaluate passive immunization efficacy.
Sheahan T, Rockx B, Donaldson E, Corti D, Baric R.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Institute for Research in Biomedicine, Bellinzona, Switzerland.