The lethal triad: SARS-CoV-2 Spike, ACE2 and TMPRSS2. Mutations in host and pathogen may affect the course of pandemic
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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 20 th 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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SciScore for 10.1101/2021.01.12.426365: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Dataset S3 of Supplementary material includes 29 sequences of SARS-CoV previously reported [26,27]The functional domains of protein were mapped by CD-search [43] while the trans-membrane and inner domains were predicted by TMHMM Server v. 2.0. [44] and confirmed by UniProtKB (ID: P0DTC2 SPIKE_SARS2). UniProtKBsuggested: (UniProtKB, RRID:SCR_004426)Molecular docking simulations: The model of isoform 1 of TMPRSS was obtained by using I-Tasser server [49] with the sequence NP_001128571.1 as input. I-Tassersuggested: (I-TASSER, RRID:SCR_014627)Results from OddPub: Thank you for sharing your data.
SciScore for 10.1101/2021.01.12.426365: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Dataset S3 of Supplementary material includes 29 sequences of SARS-CoV previously reported [26,27]The functional domains of protein were mapped by CD-search [43] while the trans-membrane and inner domains were predicted by TMHMM Server v. 2.0. [44] and confirmed by UniProtKB (ID: P0DTC2 SPIKE_SARS2). UniProtKBsuggested: (UniProtKB, RRID:SCR_004426)Molecular docking simulations: The model of isoform 1 of TMPRSS was obtained by using I-Tasser server [49] with the sequence NP_001128571.1 as input. I-Tassersuggested: (I-TASSER, RRID:SCR_014627)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Although with limitations and caveats of in silico technology, this study tries to address the question of how some mutations of the Spike protein of SARS-CoV-2 may affect the host-pathogen interactions, providing interesting insight on factors associated with a different individual susceptibility to COVID-19. To alleviate these limitations, we used a combination of bioinformatics tools, and tested different models. One year after the spread of the SARS COVID-19, its worldwide distribution remains extremely uneven. Lethality is even more inhomogeneous among and within countries. Although differences in mortality might have various causes, including access and efficiency of health systems, total number of people tested, presence and severity of symptoms in tested populations, they are so impressive that it seems legitimate to search for other factors possibly related to individuals as the elements of a population challenged with different types (wild type or mutants) of viruses. Ultimately, infectivity and lethality do not seem linearly related, and probably represent problems to be solved with different, albeit complementary, approaches. Basic aspects of epidemiology of the disease warrant some considerations: women are probably more prone to infection but often present a less severe disease. Although higher incidence of cardiac, respiratory and metabolic co-morbidities are probably responsible for more severe form of infection in men, estrogen-induced upregulation of ACE2 ex...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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