ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects

  1. Stephanie Shiers
  2. Pradipta R. Ray
  3. Andi Wangzhou
  4. Ishwarya Sankaranarayanan
  5. Claudio Esteves Tatsui
  6. Laurence D. Rhines
  7. Yan Li
  8. Megan L. Uhelski
  9. Patrick M. Dougherty
  10. Theodore J. Price

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Abstract

SARS-CoV-2 has created a global crisis. COVID-19, the disease caused by the virus, is characterized by pneumonia, respiratory distress, and hypercoagulation and can be fatal. An early sign of infection is loss of smell, taste, and chemesthesis—loss of chemical sensation. Other neurological effects of the disease have been described, but not explained. It is now apparent that many of these neurological effects (for instance joint pain and headache) can persist for at least months after infection, suggesting a sensory neuronal involvement in persistent disease. We show that human dorsal root ganglion (DRG) neurons express the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 at the RNA and protein level. We also demonstrate that SARS-CoV-2 and coronavirus-associated factors and receptors are broadly expressed in human DRG at the lumbar and thoracic level as assessed by bulk RNA sequencing. ACE2 mRNA is expressed by a subset of nociceptors that express MRGPRD mRNA, suggesting that SARS-CoV-2 may gain access to the nervous system through entry into neurons that form free nerve endings at the outermost layers of skin and luminal organs. Therefore, DRG sensory neurons are a potential target for SARS-CoV-2 invasion of the peripheral nervous system, and viral infection of human nociceptors may cause some of the persistent neurological effects seen in COVID-19.

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  1. Version published to 10.1097/j.pain.0000000000002051
  2. ScreenIT

    SciScore for 10.1101/2020.05.28.122374: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Tissue preparation: All human tissue procurement procedures were approved by the Institutional Review Boards at the University of Texas at Dallas and University of Texas MD Anderson Cancer Center.
    Randomizationnot detected.
    BlindingImages were not analyzed in a blinded fashion.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The raw image files were brightened and contrasted in Olympus CellSens software (v1.18), and then analyzed manually one cell at a time for expression of each gene target.
    CellSens
    suggested: None
    Data Analysis: Graphs were generated using GraphPad Prism version 7.01 (GraphPad Software, Inc. San Diego, CA USA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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: Please consider improving the rainbow (“jet”) colormap(s) used on pages 4, 13 and 14. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.05.28.122374 on bioRxiv