Disruption of nuclear architecture as a cause of COVID-19 induced anosmia

  1. Marianna Zazhytska
  2. Albana Kodra
  3. Daisy A. Hoagland
  4. John F. Fullard
  5. Hani Shayya
  6. Arina Omer
  7. Stuart Firestein
  8. Qizhi Gong
  9. Peter D. Canoll
  10. James E. Goldman
  11. Panos Roussos
  12. Benjamin R. tenOever
  13. Jonathan B. Overdevest
  14. Stavros Lomvardas

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Olfaction relies on a coordinated partnership between odorant flow and neuronal communication. Disruption in our ability to detect odors, or anosmia, has emerged as a hallmark symptom of infection with SARS-CoV-2, yet the mechanism behind this abrupt sensory deficit remains elusive. Here, using molecular evaluation of human olfactory epithelium (OE) from subjects succumbing to COVID-19 and a hamster model of SARS-CoV-2 infection, we discovered widespread downregulation of olfactory receptors (ORs) as well as key components of their signaling pathway. OR downregulation likely represents a non-cell autonomous effect, since SARS-CoV-2 detection in OSNs is extremely rare both in human and hamster OEs. A likely explanation for the reduction of OR transcription is the striking reorganization of nuclear architecture observed in the OSN lineage, which disrupts multi-chromosomal compartments regulating OR expression in humans and hamsters. Our experiments uncover a novel molecular mechanism by which a virus with a very selective tropism can elicit persistent transcriptional changes in cells that evade it, contributing to the severity of COVID-19.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.02.09.430314: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was approved by the ethics and Institutional Review Board of Columbia University Medical Center (IRB AAAT0689, AAAS7370).
    IACUC: Hamsters: LVG Golden Syrian hamsters (Mesocricetus auratus) were treated and euthanized in compliance with the rules and regulations of IACUC under protocol number PROTO202000113-20-0743.
    RandomizationThe experiments were not randomized and investigators were not blinded to allocation during experiments.
    BlindingThe experiments were not randomized and investigators were not blinded to allocation during experiments.
    Power Analysisnot detected.
    Sex as a biological variableOnly male hamsters were used for experiments.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    SARS-CoV-2 (clinical isolate UAS/WA1/2020) virus was propagated in Vero E6 cells in DMEM supplemented with 0.35% BSA.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Software and Algorithms
    SentencesResources
    Fluorescence-activated nuclei sorting: Frozen 1% PFA-fixed tissue was mechanically crushed using Covaris Impactor and then nuclei were extracted with OptiPrep Density Gradient Medium according to the Sigma Millipore protocol.
    Sigma Millipore
    suggested: (Penn Cell Center Stockroom, RRID:SCR_010003)
    The quality and concentration of libraries were assessed using Agilent Bioanalyzer and Qubit Quantification Kit.
    Agilent Bioanalyzer
    suggested: None
    Hi-C data processing and analysis: Raw fastq files were processed using the Juicer single CPU BETA version on AWS.
    BETA
    suggested: (BETA, RRID:SCR_007556)
    gz using BWA
    BWA
    suggested: (BWA, RRID:SCR_010910)

    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.

    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.

  2. Version published to 10.1101/2021.02.09.430314v1 on bioRxiv