"Significance
The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS)-CoV highlights the continued risk of cross-species transmission leading to epidemic disease. This manuscript describes efforts to extend surveillance beyond sequence analysis, constructing chimeric and full-length zoonotic coronaviruses to evaluate emergence potential. Focusing on SARS-like virus sequences isolated from Chinese horseshoe bats, the results indicate a significant threat posed by WIV1-CoV. Both full-length and chimeric WIV1-CoV readily replicated efficiently in human airway cultures and in vivo, suggesting capability of direct transmission to humans. In addition, while monoclonal antibody treatments prove effective, the SARS-based vaccine approach failed to confer protection. Together, the study indicates an ongoing threat posed by WIV1-related viruses and the need for continued study and surveillance...
Discussion
... In this paper, we outline a platform that leverages metagenomics data, synthetic genome design, transgenic mouse models, and therapeutic human antibodies to identify and treat potential prepandemic viruses. Focusing on SARS-like CoVs, the approach indicates that viruses using the WIV1-CoV spike protein are capable of infecting HAE cultures directly without further spike adaptation. Whereas in vivo data indicate attenuation relative to SARS-CoV, the augmented replication in the presence of human ACE2 in vivo suggests that the virus has significant pathogenic potential not captured by current small animal models. Importantly, therapeutic treatment with monoclonal antibodies suggests a Zmapp-based approach would be effective against a WIV1-CoV spike-mediated outbreak. However, failure of SARS DIV vaccine to induce protection highlights the need for continued development of additional therapeutics. Overall, the characterization of WIV1-CoV and its pathogenic potential highlight the utility of this platform in evaluating currently circulating zoonotic viruses.
Biosafety and Biosecurity.
Reported studies were initiated after the University of North Carolina Institutional Biosafety Committee approved the experimental protocol: project title: Generating infectious clones of Bat SARS-like CoVs; lab safety plan ID: 20145741; schedule G ID: 12279. These studies were initiated before the US Government Deliberative Process Research Funding Pause on Selected Gain of Function Research Involving Influenza, MERS, and SARS Viruses (www.phe.gov/s3/dualuse/Documents/gain-of-function.pdf), and the current paper has been reviewed by the funding agency, the National Institutes of Health (NIH). Continuation of these studies has been requested and approved by the NIH.
Acknowledgments
We thank Dr. Zhengli-Li Shi of the Wuhan Institute of Virology for access to bat CoV sequences and plasmid of WIV1-CoV spike protein. Research was supported by the National Institute of Allergy and Infectious Disease and the National Institute of Aging of the NIH under Awards U19AI109761 and U19AI107810 (to R.S.B.), AI1085524 (to W.A.M.), and F32AI102561 and K99AG049092 (to V.D.M.). Human airway epithelial cell cultures were supported by the National Institute of Diabetes and Digestive and Kidney Disease under Award NIH DK065988 (to S.H.R.). Support for the generation of the mice expressing human ACE2 was provided by NIH Grants AI076159 and AI079521 (to A.C.S.)."
Freely available online through the PNAS open access option.