MINIREVIEW: The journey of SARS-CoV-2: from bats to humans, across pangolins

Literature Analysis: Rocco Stirparo, Giulia Poggi; Reviewers: Valeria Montis, Giulia Poggi

The ongoing outbreak of CoViD-19 is associated with a novel coronavirus, SARS-CoV-2. Although bats (Rhinolophus affinis) are likely natural reservoirs for SARS-CoV-2, an unknown intermediate host might have facilitated transfer to humans. Results of these studies suggest that Malayan pangolins (Manis javanica), like other wild animals, could be considered as possible sources of contagion for novel Coronaviruses and it poses an important concern whether animal species should be removed from wet markets to prevent further zoonotic transmissions.

Coronaviruses have been detected in various members of the animal kingdom and, in multiple instances, they have been protagonists of zoonosis, sometimes resulting in very insidious human pathogens [3].
Bats and rodents are the most common gene source of most Alpha- and Beta- coronavirus, while birds are mostly of Gamma- and Delta-coronavirus [3]. The majority of the currently known human coronaviruses [3] and a large number of SARS-related coronaviruses have emerged from bats (Fig. 1) [5]. Indeed, bats are ideal “virus spreaders”, given their longevity, sociability, and ability to fly. In this host, coronaviruses are well adapted, non-pathogenic but with a great genetic diversity and potential to infect humans [3][4].

SARS-CoV-2 most probably did not reach humans directly from bats [1][2][3]. As for SARS-CoV and MERS-CoV, which originated in bats and then infected civets and camels, respectively, before they got transmitted to humans, it is conceivable that SARS-CoV-2 was first transferred from bats to an intermediate host (Fig. 2).

Indeed, phylogenetic relationships among Pangolin-CoV (detected in Malayan pangolins) [1][2]5, bat RaTG13 coronavirus, and human SARS-CoV-2 have been found [1][5]. The main highlights if these studies are listed below and described in Fig.4.

A) SARS-CoV-2 seems to have originated from bats, since it showed 96.2% identity to the genome sequence of BatCoV RaTG13. Pangolin-CoV showed high overall genome sequence identity to RaTG13 (90.55%) and SARS-CoV-2 (91.02%), although there was a higher identity (96.2%) between SARS-CoV-2 and RaTG13 [1][5].

B) Pangolin-CoV could have a pathogenic potential similar to SARS-CoV-2, according to the high homology between the receptor-binding domain (RBD) sequences, fundamental for recognition and infection of the host cells via ACE2 receptor. Specifically, Pangolin-CoV and SARS-CoV-2 possess identical amino acids at the five keys residues of the RBD, whereas RaTG13 only shares one amino acid with SARS-CoV-2 [1][2]. Whether the Pangolin-CoV or RaTG13 are potential infectious agents to humans remains to be determined.

C) Only SARS-CoV-2 contains a potential cleavage site for furin proteases. Upon binding of the spike (S) protein to ACE2, the enzyme furin (a host pleiotropic protease) cuts at the polybasic S1/S2 cleavage site (where S1 and S2 are the two subunits of the Spike protein), allowing the virus entry in the host cell. The presence of a furin cleavage site determines transmissibility and pathogenicity of SARS-CoV-like viruses [1] and it might explain why SARS-CoV-2 is so contagious. Instead, pangolin-CoV and all other SARS-CoVs lost the putative furin recognition sequence motif at S1/S2 cleavage site [2].

Interestingly, aside from MERS-CoV, similar furin recognition sites were also presented in some members of Alpha-, Beta-, and Gamma-coronavirus. This raises the question on whether the furin motif in SARS-CoV-2 originated from those existing S proteins or from recombination between Pangolin-CoV or RaTG13 and these other coronaviruses in an unknown intermediate host [1].

Conclusively, those studies show that many wild species represent a natural reservoir of CoVs as well as intermediate hosts and strongly suggest that handling these animals requires considerable caution, and that their sale in wet markets should be strictly prohibited. Further surveillance on natural CoVs sources in their natural environment are clearly needed to understand their role in the risk of future zoonotic transmissions.

Bibliography:

[1] Zhang T, Wu Q, Zhang Z. Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak. Curr Biol. 2020 Apr 6;30(7):1346-1351.e2.

[2] Lam TT, Shum MH, Zhu HC, Tong YG, Ni XB, Liao YS, Wei W, Cheung WY, Li WJ, Li LF, Leung GM, Holmes EC, Hu YL, Guan Y. Identifying SARS-CoV-2 related coronaviruses in Malayan pangolins. Nature. 2020 Mar 26.

[3] Ye ZW, Yuan S, Yuen KS, Fung SY, Chan CP, Jin DY. Zoonotic origins of human coronaviruses. Int J Biol Sci. 2020 Mar 15;16(10):1686-1697.

[4] Menachery VD, Yount BL Jr, Debbink K, Agnihothram S, Gralinski LE, Plante JA, Graham RL, Scobey T, Ge XY, Donaldson EF, Randell SH, Lanzavecchia A, Marasco WA, Shi ZL, Baric RS. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat Med. 2015 Dec;21(12):1508-13.

[5] Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Mar;579(7798):270-273.