For SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) is required for human cell entry by binding to the SARS-CoV-2 RBD on the S protein ( Lan et al., 2020 Shang et al., 2020 Wang et al., 2020b). Thus, evaluating the interactions between viral ligands and receptor orthologs of various animals may lead to identification of susceptible hosts. The gain of function to interact with the receptor orthologs of another species is also a prerequisite for inter-species transmission ( Su et al., 2016). Receptor binding is the key step for a virus to achieve cross-species infection and transmission ( Li et al., 2020b). To access this risk, the host range of RaTG13 needs to be investigated.
Considering the similarity between RaTG13 and SARS-CoV-2 and the devastation caused by SARS-CoV-2, RaTG13 may pose a significant threat to humans and other animals. For example, RmYN02, another bCoV, detected in Rhinolophus malayanus, shares 93.3% nucleotide identity with the SARS-CoV-2 genome and contains three-amino-acid-residue (PAA) insertions at the S1/S2 cleavage site of its S protein, which is similar to that in SARS-CoV-2 ( Zhou et al., 2020a). However, such residue insertions can occur naturally in CoVs, which may contribute to RaTG13 evolving into the causative pathogen of the next potential pandemic.
One variance of RaTG13 compared with SARS-CoV-2 is the absence of the four-residue (PRRA) insertions at the S1/S2 cleavage site on the spike (S) protein. RaTG13, sequenced from Rhinolophus affinis (intermediate horseshoe bat) in Yunnan province is the closest relative to SARS-CoV-2, with 96.2% identity of the overall genome sequence and 89.3% amino acid identity in the receptor binding domain (RBD) ( Boni et al., 2020 Wu et al., 2020a Zhou et al., 2020b). SARS-CoV-2 is closely related to several CoVs from bats ( Chan et al., 2020 Liu et al., 2021 Malik et al., 2020). SARS-CoV and MERS-CoV have caused global outbreaks in the past two decades and confirmed cases of MERS-CoV infection are still growing in the Middle East region. Increasing evidence indicates that bat CoVs (bCoVs) are the evolutionary sources of SARS-CoV (beta CoV), Middle East respiratory syndrome CoV (MERS-CoV beta CoV), swine acute diarrhea syndrome CoV (SADS-CoV alpha CoV), human CoV (HCoV)-OC43 (beta CoV), HCoV-NL63 (alpha CoV), and HCoV-229E (alpha CoV) ( Corman et al., 2015 Gao, 2018 Huynh et al., 2012 Latinne et al., 2020 Lau et al., 2005 Li et al., 2005 Smith and Wang, 2013 Wang et al., 2018), most of which can infect humans and cause disease ( Su et al., 2016). Bats are recognized as natural reservoirs of alpha and beta CoVs ( Latinne et al., 2020). CoVs are classified into four genera: alpha, beta, gamma, and delta CoVs. SARS-CoV-2 belongs to the family Coronaviridae, enveloped RNA viruses in the order Nidovirales ( ). As of March 5, 2021, the World Health Organization (WHO ) has recorded more than 114 million confirmed cases of CoV disease 2019 (COVID-19) globally and more than 2.5 million related deaths. SARS-CoV-2 later spread worldwide, causing a global pandemic. The new coronavirus (CoV) severe acute respiratory syndrome CoV 2 (SARS-CoV-2) was detected and then isolated in early 2020 ( Tan et al., 20-nCoV Outbreak Joint Field Epidemiology Investigation Team and Li, 2020 Wang et al., 2020a Zhu et al., 2020). These results elucidate the receptor binding and host adaption mechanisms of RaTG13 and emphasize the importance of continuous surveillance of coronaviruses (CoVs) carried by animal reservoirs to prevent another spillover of CoVs.Įmerging and re-emerging pathogens threaten global public health and cause tremendous economic losses ( Gao, 2018). We also found that SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus. By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501, the major position found in variants of concern (VOCs) 501Y.V1/V2/V3, plays a key role in determining the potential host range of RaTG13. Here we obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs. Bat-origin RaTG13 is currently the most phylogenetically related virus. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide, causing a global pandemic.