Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor

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Abstract
Whole-genome sequences of two novel SARS-CoV-related bat coronaviruses, in addition to a live isolate of a bat SARS-like coronavirus, are reported; the live isolate can infect human cells using ACE2, providing the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV. Peter Daszak and colleagues identify two novel coronaviruses from Chinese horseshoe bats that are closely related to severe acute respiratory syndrome coronavirus (SARS-CoV), the cause of a pandemic during 2002 and 2003. They also isolate a live virus from these bats that has high sequence identity to SARS-CoV and that can infect human cells using ACE2, the same receptor that is used by SARS-CoV. The results provide the strongest evidence to date that horseshoe bats are natural reservoirs of SARS-CoV. The 2002–3 pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV) was one of the most significant public health events in recent history1. An ongoing outbreak of Middle East respiratory syndrome coronavirus2 suggests that this group of viruses remains a key threat and that their distribution is wider than previously recognized. Although bats have been suggested to be the natural reservoirs of both viruses3,4,5, attempts to isolate the progenitor virus of SARS-CoV from bats have been unsuccessful. Diverse SARS-like coronaviruses (SL-CoVs) have now been reported from bats in China, Europe and Africa5,6,7,8, but none is considered a direct progenitor of SARS-CoV because of their phylogenetic disparity from this virus and the inability of their spike proteins to use the SARS-CoV cellular receptor molecule, the human angiotensin converting enzyme II (ACE2)9,10. Here we report whole-genome sequences of two novel bat coronaviruses from Chinese horseshoe bats (family: Rhinolophidae) in Yunnan, China: RsSHC014 and Rs3367. These viruses are far more closely related to SARS-CoV than any previously identified bat coronaviruses, particularly in the receptor binding domain of the spike protein. Most importantly, we report the first recorded isolation of a live SL-CoV (bat SL-CoV-WIV1) from bat faecal samples in Vero E6 cells, which has typical coronavirus morphology, 99.9% sequence identity to Rs3367 and uses ACE2 from humans, civets and Chinese horseshoe bats for cell entry. Preliminary in vitro testing indicates that WIV1 also has a broad species tropism. Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs. They also highlight the importance of pathogen-discovery programs targeting high-risk wildlife groups in emerging disease hotspots as a strategy for pandemic preparedness.
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