Functional comparison of SARS-CoV-2 with closely related pangolin and bat coronaviruses

Abstract

The origin and intermediate host for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is yet to be determined. Coronaviruses found to be closely related to SARS-CoV-2 include RaTG13 derived from bat and two clusters (PCoV-GD and PCoV-GX) of coronaviruses identified in pangolin. Here, we studied the infectivity and antigenicity patterns of SARS-CoV-2 and the three related coronaviruses. Compared with the other three viruses, RaTG13 showed almost no infectivity to a variety of cell lines. The two pangolin coronaviruses and SARS-CoV-2 showed similar infectious activity. However, in SARS-CoV-2-susceptible cell lines, the pangolin coronaviruses presented even higher infectivity. The striking difference between the SARS-CoV-2 and pangolin coronaviruses is that the latter can infect porcine cells, which could be partially attributed to an amino acid difference at the position of 498 of the spike protein. The infection by SARS-CoV-2 was mainly mediated by Furin and TMPRSS2, while PCoV-GD and PCoV-GX mainly depend on Cathepsin L. Extensive cross-neutralization was found between SARS-CoV-2 and PCoV-GD. However, almost no cross-neutralization was observed between PCoV-GX and SARS-CoV-2 or PCoV-GD. More attention should be paid to pangolin coronaviruses and to investigate the possibility of these coronaviruses spreading across species to become zoonoses among pigs or humans.

Natural and Experimental SARS-CoV-2 Infection in Domestic and Wild Animals

“…SARS-CoV-2 was found to be most closely related genetically to a horseshoe bat coronavirus called CoV-RaTG13 that was isolated in Yunnan province, China, with 96.2% nucleotide identity between the two viruses [ 1 ]. An intermediate host for SARS-CoV-2 has not been conclusively identified, although pangolins have emerged as a potential culprit [ 27 , 28 , 29 ]. Interestingly, SARS-CoV-2 contains a spike protein receptor binding domain (RBD) and polybasic furin cleavage site that are distinct from CoV-RaTG13; the RBD is directly involved in its cellular entry mechanism through binding to the human angiotensin-converting enzyme 2 (hACE2) receptor, followed by cleavage at the furin cleavage site by the TMPRRS2 transmembrane serine protease [ 1 , 30 , 31 ].…”

SARS-CoV-2 gained the unique spike protein S1-N-Terminal Domain from the promising pangolins mixing vessel: A novel clue for the pandemic outbreak

“…Moreover, SARS-CoV-2 has been shown to infect efficiently 293T and Vero cells without human ACE2 transfection 12,40 . Therefore, it could be inferred that the SARS-CoV-2-S1-RBD and FCS might be the cause for the severity of the infection and in addition, some other factors also contribute to the increased transmissibility of infection in humans which is the hallmark for the SARS-CoV-2 in comparison to SARS-CoV-1 and MERS-CoV.…”

“…The pseudotyped virus of S protein RatG13 has a poor ability to infect many cell types, including bat and human cells 23,40 . The RaTG13 is the only one bat virus RNA sequence having the Type-I-S1-NTD remains unknown.…”

“…The RaTG13 is the only one bat virus RNA sequence having the Type-I-S1-NTD remains unknown. It could be due to (i) Reverse zoonosis of human-specific Type-I-S1-NTD to bats, as SARS-CoV-2 is known to cause reverse zoonosis [57][58][59][60][61][62][63] ; or (ii) Contamination of human virus to bat sample during sample collection, transport, storage, and sample processing, and this theory might be disproved by isolation of the virus and experimental infection; or (iii) The RaTG13 virus may spontaneously evolve in bats; however, the RaTG13 (with Type-I-S1-NTD) and Pangolin/GX/2018 lineage (with Type-I-like-S1-NTD) S gene pseudotyped viruses fail to infect bat cells 40 ; whereas, Pangolin/Guangdong/2019 lineage (with TypeII-like-S1-NTD) efficiently infect the bat cells 40 . Therefore, it can be inferred that the Type-I-S1-NTD is the most potential for enhancing human adaptation.…”

The high diversity of SARS-CoV-2-related coronaviruses in pangolins alters potential ecological risks

“…Currently, M. javanica is the only known pangolin species that harbors coronaviruses closely related to SARS-CoV-2. Although the pangolin-CoVs tend to be more distantly related to SARS-CoV-2 than the aforementioned bat-derived SC2r-CoVs, recent studies show that the receptor-binding domain (RBD) of both pangolin-CoV sublineages can potentially bind the human ACE2 receptor ( Dicken et al, 2021 ; Guo et al, 2021 ; Nie et al, 2021 ; Niu et al, 2021 ; Zhang et al, 2021 ), raising concerns about the potential risks of spillover of these pangolin-CoVs to humans.…”