SARS-CoV-2 entry into human and animal host cells: Should we pay attention just to the ACE2 receptor?

This commentary addresses an interesting article focused on a machine learning-based approach, which was successfully employed to predict mammalian hosts' susceptibility to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, along with the zoonotic risk posed by them [1].

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The three-dimensional model described by the aforementioned authors enabled prediction of the zoonotic potential of SARS-CoV-2 for more than 5000 domestic and wild mammals, with the obtained predictions being additionally corroborated by in vivo studies [1]. One of the main reasons underlying this work was represented by the comparatively much fewer mammalian species for which the primary amino acid sequences of their angiotensin-converting enzyme 2 (ACE2) viral host cell receptor are currently available. 

In this respect, however, adequate emphasis should be also placed upon the fact that a number of discrepancies have been reported between ACE2-expressing cells, on one side, and tissue tropism of SARS-CoV-2, on the other, with very low ACE2 expression levels having been found in respiratory and olfactory epithelial cells, despite their extremely frequent, if not constant, targeting by this viral pathogen [2].

Noteworthy, two independent studies published in November 2020 in Science have shown that neuropilin-1 (NRP1), which is consistently expressed by respiratory, olfactory epithelial and endothelial cells, binds (similarly to ACE2) the furin-cleaved S1 fragment of SARS-CoV-2 spike glycoprotein, thereby potentiating infectivity and allowing viral entry into host cells [3,4]. This could also explain why a number of viruses such as human T-cell lymphotropic virus type 1 [5] and Epstein–Barr virus [6] use NRP1 for gaining entrance into susceptible host cells, given its high expression on epithelia facing the external environment and its role in enabling cell, vascular and tissue colonization.

Within this framework, it would be interesting to comparatively investigate if and to what extent the different body cells and tissues from humans as well as from a number of SARS-CoV-2-susceptible mammals—either naturally/experimentally or suspectedly, based upon the herein commented machine learning approach [1]—express ACE2 and NRP1 simultaneously. Furthermore, the comparative study of the degree of primary amino acid sequence homology between human and animal ACE2 and NRP1 viral host cell receptors/coreceptors would probably clarify the SARS-CoV-2 susceptibility of the different species under investigation. This, in turn, could also allow a given animal species to act as a potentially valuable model in the comparative pathogenetic study of human SARS-CoV-2 infection, thus elucidating past and future ‘trajectories’ of this threatening viral agent, with special emphasis on its origin and on its ‘spillovers and spillbacks' from animals to mankind (and viceversa).


1. Fischhoff IR, Castellanos AA, Rodrigues JP, Varsani A, Han BA. 2021. Predicting the zoonotic capacity of mammals to transmit SARS-CoV-2. Proc. R. Soc. B 288, 20211651. (10.1098/rspb.2021.1651).
2. Hikmet F, Méar L, Edvinsson Å, Micke P, Uhlén M, Lindskog C. 2020. The protein expression profile of ACE2 in human tissues. Mol. Syst. Biol. 16, e9610. (10.15252/msb.20209610).
3. Cantuti-Castelvetri L, et al. 2020. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 370, 856-860. (10.1126/science.abd2985).
4. Daly JL, et al. 2020. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science 370, 861-865. (10.1126/science.abd3072).
5. Ghez D, et al. 2006. Neuropilin-1 is involved in human T-cell lymphotropic virus type 1 entry. J. Virol. 80, 6844-6854. (10.1128/JVI.02719-05).
6. Wang HB, et al. 2015. Neuropilin 1 is an entry factor that promotes EBV infection of nasopharyngeal epithelial cells. Nat. Commun. 6, 6240. (10.1038/ncomms7240).

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