Human Identical Sequences of SARS-CoV-2 Promote Clinical Progression of COVID-19 by Upregulating Hyaluronan via NamiRNA-Enhancer Network

  1. Wei Li
  2. Shuai Yang
  3. Peng Xu
  4. Dapeng Zhang
  5. Ying Tong
  6. Lu Chen
  7. Ben Jia
  8. Ang Li
  9. Daoping Ru
  10. Baolong Zhang
  11. Mengxing Liu
  12. Cheng Lian
  13. Cancan Chen
  14. Weihui Fu
  15. Songhua Yuan
  16. Xiaoguang Ren
  17. Ying Liang
  18. Zhicong Yang
  19. Wenxuan Li
  20. Shaoxuan Wang
  21. Xiaoyan Zhang
  22. Hongzhou Lu
  23. Jianqing Xu
  24. Hailing Wang
  25. Wenqiang Yu

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Abstract

The COVID-19 pandemic is a widespread and deadly public health crisis. The pathogen SARS-CoV-2 replicates in the lower respiratory tract and causes fatal pneumonia. Although tremendous efforts have been put into investigating the pathogeny of SARS-CoV-2, the underlying mechanism of how SARS-CoV-2 interacts with its host is largely unexplored. Here, by comparing the genomic sequences of SARS-CoV-2 and human, we identified five fully conserved elements in SARS-CoV-2 genome, which were termed as “human identical sequences (HIS)”. HIS are also recognized in both SARS-CoV and MERS-CoV genome. Meanwhile, HIS-SARS-CoV-2 are highly conserved in the primate. Mechanically, HIS-SARS-CoV-2, behaving as virus-derived miRNAs, directly target to the human genomic loci and further interact with host enhancers to activate the expression of adjacent and distant genes, including cytokines gene and angiotensin converting enzyme II ( ACE2 ), a well-known cell entry receptor of SARS-CoV-2, and hyaluronan synthase 2 ( HAS2 ), which further increases hyaluronan formation. Noteworthily, hyaluronan level in plasma of COVID-19 patients is tightly correlated with severity and high risk for acute respiratory distress syndrome (ARDS) and may act as a predictor for the progression of COVID-19. HIS antagomirs, which downregulate hyaluronan level effectively, and 4-Methylumbelliferone (MU), an inhibitor of hyaluronan synthesis, are potential drugs to relieve the ARDS related ground-glass pattern in lung for COVID-19 treatment. Our results revealed that unprecedented HIS elements of SARS-CoV-2 contribute to the cytokine storm and ARDS in COVID-19 patients. Thus, blocking HIS-involved activating processes or hyaluronan synthesis directly by 4-MU may be effective strategies to alleviate COVID-19 progression.

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  1. ScreenIT

    SciScore for 10.1101/2020.11.04.361576: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    After sonication, sheared chromatin was immunoprecipitated with H3K27ac antibody (Abcam, ab177178) and Protein A magnetic beads (Invitrogen, 10002D) overnight at 4°C.
    H3K27ac
    suggested: (Abcam Cat# ab177178, RRID:AB_2828007)
    Experimental Models: Cell Lines
    SentencesResources
    Also, the antagomirs for HIS-SARS2-1, HIS-SARS2-2, HIS-SARS2-3, HIS-SARS2-4, HIS-SARS2-5, and HIS-SARS-1 were purchased from Guangzhou RiboBio Co., Ltd.
    HIS-SARS-1
    suggested: None
    Lentivirus Package and Cell Screening: We co-transfected pCDH-pre-HIS, pSPAX2, and pMD2G plasmids into HEK293T cells in a ratio of 4:3:1.2 and collected the virus supernatant by filtering cell culture supernatant with 0.45 filters at 48 hours after changing the serum-containing medium.
    HEK293T
    suggested: None
    Software and Algorithms
    SentencesResources
    Viral Genome and Human Genome Blast: Human reference genome (hg38) was obtained from GenBank using Blastn (Chen et al., 2015) with SARS-CoV-2 as a query.
    Blastn
    suggested: (BLASTN, RRID:SCR_001598)
    The detail parameters were chosen as follow: 1) The Maximum number of hits to report:500; 2) Maximum E-value for reported alignments: 10; 3) Word size for seeding alignments: 11; 4) the match/Mismatch scores: 1,-3; 5) Gap penalties: Openging:2, Extension:2; 6) Filter low complexity regions; 7) Filter query sequences using RepeatMasker.
    RepeatMasker
    suggested: (RepeatMasker, RRID:SCR_012954)
    Gene Function Annotation: KEGG (Kyoto Encyclopedia of Genes and Genomes) and Gene Ontology analysis on the surrounding (±500kb) genes of the identical sequences of HIS in human genome were performed using DAVID (Huang da et al., 2009).
    KEGG
    suggested: (KEGG, RRID:SCR_012773)
    DAVID
    suggested: (DAVID, RRID:SCR_001881)

    Results from OddPub: Thank you for sharing your data.

    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.

    About SciScore

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  2. Version published to 10.1101/2020.11.04.361576 on bioRxiv