The lethal triad: SARS-CoV-2 Spike, ACE2 and TMPRSS2. Mutations in host and pathogen may affect the course of pandemic

Abstract

Variants of SARS-CoV-2 have been identified rapidly after the beginning of pandemic. One of them, involving the spike protein and called D614G, represents a substantial percentage of currently isolated strains. While research on this variant was ongoing worldwide, on December 20th 2020 the European Centre for Disease Prevention and Control reported a Threat Assessment Brief describing the emergence of a new variant of SARS-CoV-2, named B.1.1.7, harboring multiple mutations mostly affecting the Spike protein. This viral variant has been recently associated with a rapid increase in COVID-19 cases in South East England, with alarming implications for future virus transmission rates. Specifically, of the nine amino acid replacements that characterize the Spike in the emerging variant, four are found in the region between the Fusion Peptide and the RBD domain (namely the already known D614G, together with A570D, P681H, T716I), and one, N501Y, is found in the Spike Receptor Binding Domain – Receptor Binding Motif (RBD-RBM). In this study, by using in silico biology, we provide evidence that these amino acid replacements have dramatic effects on the interactions between SARS-CoV-2 Spike and the host ACE2 receptor or TMPRSS2, the protease that induces the fusogenic activity of Spike. Mostly, we show that these effects are strongly dependent on ACE2 and TMPRSS2 polymorphism, suggesting that dynamics of pandemics are strongly influenced not only by virus variation but also by host genetic background.

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“… 58 Using a similar approach, Yurkovetskiy et al 59 showed how D614G changes affect the conformation of the S1 domain in the SARS-CoV-2 spike; the association rate between D614G and ACE2 being slower than that between D614 and ACE2 and the dissociation rate of D614G being faster and resulting in a lower affinity. In silico studies by Calcagnile et al 60 predicted that D614G replacement could drastically change the peptide secondary structure by replacing the (intracellular) C-terminal β-sheet with the α-helix in the region close to the mutation with a consequent increase in flexibility and variations in affinity between ACE2 and the D614G spike. However, unlike the T478K mutation, the D614G mutation is peculiar to both variants studied here.…”