SARS-like cluster of circulating bat coronavirus pose threat for human emergence

The emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome (MERS)-CoV underscores the threat of cross-species transmission events leading to outbreaks in humans. In this study, we examine the disease potential for SARSlike CoVs currently circulating in Chinese horseshoe bat populations. Utilizing the SARS-CoV infectious clone, we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse adapted SARS-CoV backbone. The results indicate that group 2b viruses encoding the SHC014 spike in a wild type backbone can efficiently utilize multiple ACE2 receptor orthologs, replicate efficiently in primary human airway cells, and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from CoVs utilizing the novel spike protein. Importantly, based on these findings, we synthetically rederived an Corresponding Authors: Ralph S. Baric (rbaric@email.unc.edu); Vineet D. Menachery (vineet@email.unc.edu). Author Contributions VDM designed, coordinated, performed experiment, completed analysis, and wrote the manuscript. BLY designed infectious clone and recovered chimeric viruses. SA completed neutralization assays. LEG helped perform mouse experiments, TS and JAP completed mouse experiments and plaque assays. XG performed pseudotyping experiments. KD generated structural figures and predictions. ED generated phylogenetic analysis. RLG completed RNA analysis. SHR provided primary human airway epithelial cultures. AL and WM provided critical monoclonal antibody reagents. ZLS provided SHC014 spike sequences and plasmids. RSB designed experiments and wrote manuscript. The authors declare no competing financial interest. HHS Public Access Author manuscript Nat Med. Author manuscript; available in PMC 2016 June 01. Published in final edited form as: Nat Med. 2015 December ; 21(12): 1508–1513. doi:10.1038/nm.3985. A uhor M anscript