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Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved October 14, 2008
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↵1M.M.B and R.L.G. contributed equally to this work. (received for review August 18, 2008)
Abstract
Defining prospective pathways by which zoonoses evolve and emerge as human pathogens is critical for anticipating and controlling both natural and deliberate pandemics. However, predicting tenable pathways of animal-to-human movement has been hindered by challenges in identifying reservoir species, cultivating zoonotic organisms in culture, and isolating full-length genomes for cloning and genetic studies. The ability to design and recover pathogens reconstituted from synthesized cDNAs has the potential to overcome these obstacles by allowing studies of replication and pathogenesis without identification of reservoir species or cultivation of primary isolates. Here, we report the design, synthesis, and recovery of the largest synthetic replicating life form, a 29.7-kb bat severe acute respiratory syndrome (SARS)-like coronavirus (Bat-SCoV), a likely progenitor to the SARS-CoV epidemic. To test a possible route of emergence from the noncultivable Bat-SCoV to human SARS-CoV, we designed a consensus Bat-SCoV genome and replaced the Bat-SCoV Spike receptor-binding domain (RBD) with the SARS-CoV RBD (Bat-SRBD). Bat-SRBD was infectious in cell culture and in mice and was efficiently neutralized by antibodies specific for both bat and human CoV Spike proteins. Rational design, synthesis, and recovery of hypothetical recombinant viruses can be used to investigate mechanisms of transspecies movement of zoonoses and has great potential to aid in rapid public health responses to known or predicted emerging microbial threats.
Footnotes
- 2To whom correspondence may be addressed. E-mail: rbaric{at}email.unc.edu or mark.denison{at}vanderbilt.edu
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Author contributions: M.M.B., R.L.G., E.F.D., R.S.B., and M.R.D. designed research; M.M.B., R.L.G., E.F.D., B.R., and A.C.S. performed research; R.L.G., E.F.D., T.S., R.J.P., D.C., and R.E.J. contributed new reagents/analytic tools; M.M.B., R.L.G., E.F.D., B.R., A.C.S., R.J.P., and R.S.B. analyzed data; and M.M.B., R.L.G., R.S.B., and M.R.D. wrote the paper.
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Conflict of interest statement: R.E.J. is a coinventor of the Venezuelan Equine Encephalitis (VEE) expression vector technology and holds an equity interest in AlphaVax, Inc., the company that has licensed this technology from the University of North Carolina.
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This article is a PNAS Direct Submission.
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Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. FJ211859 and FJ211860).
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This article contains supporting information online at www.pnas.org/cgi/content/full/0808116105/DCSupplemental.
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Freely available online through the PNAS open access option.
- © 2008 by The National Academy of Sciences of the USA
Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice
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