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Mechanisms of zoonotic severe acute respiratory syndrome coronavirus host range expansion in human airway epithelium.
J Virol. 2008 Mar; 82(5):2274-85.JV

Abstract

In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) emerged and caused over 8,000 human cases of infection and more than 700 deaths worldwide. Zoonotic SARS-CoV likely evolved to infect humans by a series of transmission events between humans and animals for sale in China. Using synthetic biology, we engineered the spike protein (S) from a civet strain, SZ16, into our epidemic strain infectious clone, creating the chimeric virus icSZ16-S, which was infectious but yielded progeny viruses incapable of propagating in vitro. After introducing a K479N mutation within the S receptor binding domain (RBD) of SZ16, the recombinant virus (icSZ16-S K479N) replicated in Vero cells but was severely debilitated in growth. The in vitro evolution of icSZ16-S K479N on human airway epithelial (HAE) cells produced two viruses (icSZ16-S K479N D8 and D22) with enhanced growth on HAE cells and on delayed brain tumor cells expressing the SARS-CoV receptor, human angiotensin I converting enzyme 2 (hACE2). The icSZ16-S K479N D8 and D22 virus RBDs contained mutations in ACE2 contact residues, Y442F and L472F, that remodeled S interactions with hACE2. Further, these viruses were neutralized by a human monoclonal antibody (MAb), S230.15, but the parent icSZ16-S K479N strain was eight times more resistant than the mutants. These data suggest that the human adaptation of zoonotic SARS-CoV strains may select for some variants that are highly susceptible to select MAbs that bind to RBDs. The epidemic, icSZ16-S K479N, and icSZ16-S K479N D22 viruses replicate similarly in the BALB/c mouse lung, highlighting the potential use of these zoonotic spike SARS-CoVs to assess vaccine or serotherapy efficacy in vivo.

Authors+Show Affiliations

Department of Epidemiology, 2107 McGavran-Greenberg, CB#7435, University of North Carolina, Chapel Hill, NC 27699-7435, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18094188

Citation

Sheahan, Timothy, et al. "Mechanisms of Zoonotic Severe Acute Respiratory Syndrome Coronavirus Host Range Expansion in Human Airway Epithelium." Journal of Virology, vol. 82, no. 5, 2008, pp. 2274-85.
Sheahan T, Rockx B, Donaldson E, et al. Mechanisms of zoonotic severe acute respiratory syndrome coronavirus host range expansion in human airway epithelium. J Virol. 2008;82(5):2274-85.
Sheahan, T., Rockx, B., Donaldson, E., Sims, A., Pickles, R., Corti, D., & Baric, R. (2008). Mechanisms of zoonotic severe acute respiratory syndrome coronavirus host range expansion in human airway epithelium. Journal of Virology, 82(5), 2274-85.
Sheahan T, et al. Mechanisms of Zoonotic Severe Acute Respiratory Syndrome Coronavirus Host Range Expansion in Human Airway Epithelium. J Virol. 2008;82(5):2274-85. PubMed PMID: 18094188.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms of zoonotic severe acute respiratory syndrome coronavirus host range expansion in human airway epithelium. AU - Sheahan,Timothy, AU - Rockx,Barry, AU - Donaldson,Eric, AU - Sims,Amy, AU - Pickles,Raymond, AU - Corti,Davide, AU - Baric,Ralph, Y1 - 2007/12/19/ PY - 2007/12/21/pubmed PY - 2008/4/1/medline PY - 2007/12/21/entrez SP - 2274 EP - 85 JF - Journal of virology JO - J Virol VL - 82 IS - 5 N2 - In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) emerged and caused over 8,000 human cases of infection and more than 700 deaths worldwide. Zoonotic SARS-CoV likely evolved to infect humans by a series of transmission events between humans and animals for sale in China. Using synthetic biology, we engineered the spike protein (S) from a civet strain, SZ16, into our epidemic strain infectious clone, creating the chimeric virus icSZ16-S, which was infectious but yielded progeny viruses incapable of propagating in vitro. After introducing a K479N mutation within the S receptor binding domain (RBD) of SZ16, the recombinant virus (icSZ16-S K479N) replicated in Vero cells but was severely debilitated in growth. The in vitro evolution of icSZ16-S K479N on human airway epithelial (HAE) cells produced two viruses (icSZ16-S K479N D8 and D22) with enhanced growth on HAE cells and on delayed brain tumor cells expressing the SARS-CoV receptor, human angiotensin I converting enzyme 2 (hACE2). The icSZ16-S K479N D8 and D22 virus RBDs contained mutations in ACE2 contact residues, Y442F and L472F, that remodeled S interactions with hACE2. Further, these viruses were neutralized by a human monoclonal antibody (MAb), S230.15, but the parent icSZ16-S K479N strain was eight times more resistant than the mutants. These data suggest that the human adaptation of zoonotic SARS-CoV strains may select for some variants that are highly susceptible to select MAbs that bind to RBDs. The epidemic, icSZ16-S K479N, and icSZ16-S K479N D22 viruses replicate similarly in the BALB/c mouse lung, highlighting the potential use of these zoonotic spike SARS-CoVs to assess vaccine or serotherapy efficacy in vivo. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/18094188/Mechanisms_of_zoonotic_severe_acute_respiratory_syndrome_coronavirus_host_range_expansion_in_human_airway_epithelium_ L2 - https://journals.asm.org/doi/10.1128/JVI.02041-07?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -