Negative regulation of ACE2 by interferons in vivo and its genetic control

  1. M. Azim Ansari
  2. Emanuele Marchi
  3. Narayan Ramamurthy
  4. Dominik Aschenbrenner
  5. Carl-Philipp Hackstein
  6. STOP-HCV consortium, ISARIC-4C Investigators
  7. Shang-Kuan Lin
  8. Rory Bowden
  9. Eshita Sharma
  10. Vincent Pedergnana
  11. Suresh Venkateswaran
  12. Subra Kugathasan
  13. Angela Mo
  14. Greg Gibson
  15. Graham Cooke
  16. John McLauchlan
  17. Eleanor Barnes
  18. John Kenneth Baillie
  19. Sarah Teichmann
  20. Alex Mentzer
  21. John Todd
  22. Julian Knight
  23. Holm Uhlig
  24. Paul Klenerman

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Abstract

The SARS-CoV-2 pandemic has resulted in widespread morbidity and mortality globally. ACE2 is a receptor for SARS-CoV-2 and differences in expression may affect susceptibility to COVID-19. Using HCV-infected liver tissue from 195 individuals, we discovered that among genes negatively correlated with ACE2 , interferon signalling pathways were highly enriched and observed down-regulation of ACE2 after interferon-alpha treatment. Negative correlation was also found in the gastrointestinal tract and in lung tissue from a murine model of SARS-CoV-1 infection suggesting conserved regulation of ACE2 across tissue and species. Performing a genome-wide eQTL analysis, we discovered that polymorphisms in the interferon lambda ( IFNL ) region are associated with ACE2 expression. Increased ACE2 expression in the liver was also associated with age and presence of cirrhosis. Polymorphisms in the IFNL region may impact not only antiviral responses but also ACE2 with potential consequences for clinical outcomes in distinct ethnic groups and with implications for therapeutic interventions.

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    SciScore for 10.1101/2020.04.26.20080408: (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
    Trimmed read pairs were mapped to human genome GRCh37 using HISAT2 version 2.0.0-beta45.
    HISAT2
    suggested: (HISAT2, RRID:SCR_015530)
    To test for enrichment we used enrichGO function from the clusterProfiler package49, limiting the analysis to GO “biological process” class and maximum gene set size of 500.
    clusterProfiler
    suggested: (clusterProfiler, RRID:SCR_016884)
    BOSON liver ACE2 expression and RISK ACE2 expression positively and negatively correlated gene sets were intersected based on Entrez gene identifiers using Cytoscape (version 3.7.1) and visualized using the Cytoscape Venn and Euler Diagrams (Version 1.0.3)
    Entrez
    suggested: (Entrez, RRID:SCR_016640)
    Cytoscape
    suggested: (Cytoscape, RRID:SCR_003032)
    Functionally grouped networks of terms and pathways were analysed using the Cytoscape (version 3.7.1) ClueGO (version 2.5.6) and CluePedia (version 1.5.6) plug-in52.
    ClueGO
    suggested: (ClueGO, RRID:SCR_005748)
    CluePedia
    suggested: (CluePedia Cytoscape plugin, RRID:SCR_015784)
    The analysis was performed by accessing the Gene Ontology Annotation (GOA) Database for Biologic processes, Cellular components, Immune system processes and Molecular function, the Reactome pathways database (https://reactome.org/) and the KEGG database (https://www.genome.jp/kegg/pathway.html).
    Reactome
    suggested: (Reactome, RRID:SCR_003485)
    KEGG
    suggested: (KEGG, RRID:SCR_012773)
    Resources for statistical analysis and data visualization: Prism version 8.0 (GraphPad Software) Excel for Mac Version 15.32
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Morpheus (https://software.broadinstitute.org/morpheus/) R (Version 3.6.1
    https://software.broadinstitute.org/morpheus/
    suggested: (Morpheus by Broad Institute, RRID:SCR_017386)
    GENESIS cohort: GENESIS is funded by the National Institute of Diabetes and Digestive and Kidney Diseases and managed by Emory University for the recruitment of self-identified African American subjects with IBD53.
    GENESIS
    suggested: (Genesis, RRID:SCR_015775)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The functional link between the locus and the phenotypes has not been fully defined, in part due to limitations in detection of IFNL proteins and mRNAs in the liver biopsies of patients with chronic HCV infection 25,26. Interferon lambda receptor (IFNLR1) is largely restricted to tissues of epithelial origin27,28, therefore, IFN-λ proteins (type III IFN) may have evolved specifically to protect the epithelium. Overall, INFL genes lead to a pattern of gene expression which is similar to type I interferon genes, but the time course and pattern of expression may vary10. This has been explored in HCV, where a slower, but sustained impact of IFNL signalling is seen29. In vitro studies have revealed that ISG expression and anti-viral activity induced by recombinant IFNL4 are comparable to that induced by IFNL330, although the tight regulation of IFNL431 may impact on its ability to induce a rapid antiviral state32, 22. However, once established, the IFNL4 transcriptional module may also be highly sustained (as seen here and in other HCV cohorts33) and also noted elsewhere, e.g. after childbirth34. In mice, the type III IFN response is restricted largely to mucosal epithelial tissues, with the lung epithelium responding to both type I and III IFNs35 and intestinal epithelial cells responding exclusively to type III IFNs. Among nonhematopoietic cells, epithelial cells are potent producers of type III IFNs. In mouse models, type III IFNs seem to be the primary type of IFN found in the...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT01962441CompletedSOF (Sovaldi®) +RBV for 16 or 24 Weeks and SOF+RBV+Peg-IFN f…

    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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  2. Version published to 10.1101/2020.04.26.20080408 on medRxiv