A Path toward SARS-CoV-2 Attenuation: Metabolic Pressure on CTP Synthesis Rules the Virus Evolution

  1. Zhihua Ou
  2. Christos Ouzounis
  3. Daxi Wang
  4. Wanying Sun
  5. Junhua Li
  6. Weijun Chen
  7. Philippe Marlière
  8. Antoine Danchin

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Abstract

In the context of the COVID-19 pandemic, we describe here the singular metabolic background that constrains enveloped RNA viruses to evolve toward likely attenuation in the long term, possibly after a step of increased pathogenicity. Cytidine triphosphate (CTP) is at the crossroad of the processes allowing SARS-CoV-2 to multiply, because CTP is in demand for four essential metabolic steps. It is a building block of the virus genome, it is required for synthesis of the cytosine-based liponucleotide precursors of the viral envelope, it is a critical building block of the host transfer RNAs synthesis and it is required for synthesis of dolichol-phosphate, a precursor of viral protein glycosylation. The CCA 3′-end of all the transfer RNAs required to translate the RNA genome and further transcripts into the proteins used to build active virus copies is not coded in the human genome. It must be synthesized de novo from CTP and ATP. Furthermore, intermediary metabolism is built on compulsory steps of synthesis and salvage of cytosine-based metabolites via uridine triphosphate that keep limiting CTP availability. As a consequence, accidental replication errors tend to replace cytosine by uracil in the genome, unless recombination events allow the sequence to return to its ancestral sequences. We document some of the consequences of this situation in the function of viral proteins. This unique metabolic setup allowed us to highlight and provide a raison d’être to viperin, an enzyme of innate antiviral immunity, which synthesizes 3ʹ-deoxy-3′,4ʹ-didehydro-CTP as an extremely efficient antiviral nucleotide.

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  1. Version published to 10.1093/gbe/evaa229
  2. ScreenIT

    SciScore for 10.1101/2020.06.20.162933: (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
    SentencesResources
    The genomes were aligned using MAFFT v7.427 (109) and manually checked with BioEdit.
    MAFFT
    suggested: (MAFFT, RRID:SCR_011811)
    BioEdit
    suggested: (BioEdit, RRID:SCR_007361)
    Phylogeny reconstruction: Phylogenetic tree of the 89 representative coronaviruses was inferred using the Maximum Likelihood (ML) method implemented in IQ-TREE v1.6.12 with the GTR+F+I+G4 substitution model determined by ModelFinder (111–113).
    IQ-TREE
    suggested: (IQ-TREE, RRID:SCR_017254)
    Gap-based alignment: The full alignment of the 89 reference strains was used to generate a tree, using FastTree 2.1.10 (115) (with gamma distribution and the nucleotide option on – namely with the command options -gamma -nt), on the NGPhylogeny.fr server (116).
    FastTree
    suggested: (FastTree, RRID:SCR_015501)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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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  3. Version published to 10.1101/2020.06.20.162933v1 on bioRxiv