Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants

  1. Mengfei Chen
  2. Andrew Pekosz
  3. Jason S. Villano
  4. Wenjuan Shen
  5. Ruifeng Zhou
  6. Heather Kulaga
  7. Zhexuan Li
  8. Amy Smith
  9. Asiana Gurung
  10. Sarah E. Beck
  11. Kenneth W. Witwer
  12. Joseph L. Mankowski
  13. Murugappan Ramanathan
  14. Nicholas R. Rowan
  15. Andrew P. Lane

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Abstract

SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in nasal tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variant revealed that SARS-CoV-2 WA1 or Delta infect a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possessed broader cellular invasion capacity into the submucosa, while Omicron displayed enhanced nasal respiratory infection and longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon were more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa were accompanied by a decline of phagocytosis-related genes. Further, robust basal stem cell activation contributed to neuroepithelial regeneration and restored ACE2 expression postinfection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration after infection. The shifting characteristics of viral infection at the airway portal provide insight into the variability of COVID-19 clinical features, particularly long COVID, and may suggest differing strategies for early local intervention.

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  1. Version published to 10.1172/jci174439
  2. ScreenIT

    SciScore for 10.1101/2022.04.12.487379: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Human nasal explant in vitro infection: The research protocol involving human specimens was approved by the Johns Hopkins institutional review board, and all subjects provided signed informed consent.
    Consent: Human nasal explant in vitro infection: The research protocol involving human specimens was approved by the Johns Hopkins institutional review board, and all subjects provided signed informed consent.
    IACUC: Animal experimental procedures were approved by the Animal Care and Use Committee at the Johns Hopkins University.
    Sex as a biological variable6 control (2 females and 4 males ranged from 45 to 63 years old) and 27 CRS biopsies (11 females and 16 males ranged from 25 to 76 years old) were used for detailed immunohistochemistry analysis.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The following primary antibodies was used: Rabbit anti-SARS-CoV-2 Nucleoprotein (1:200, Novus, NB100-56576)
    anti-SARS-CoV-2
    suggested: (Novus Cat# NB100-56576, RRID:AB_838838)
    Goat anti-ACE2 (1:100, R&D, AF933, for human samples), Rabbit anti-ACE2 (1:100
    anti-ACE2
    suggested: (Novus Cat# NB100-55793, RRID:AB_837486)
    , R&D MAB1420); Chicken anti-Vimentin (Novus NB300-223); Goat anti-Foxj1 (1:200, R&D AF3619); Mouse anti-NeuN (1:1000, BioLegend,
    anti-NeuN
    suggested: None
    The donkey-derived Alexa Fluor-conjugated secondary antibodies included anti-mouse 488 (A21202, Invitrogen); anti-Rat 488 (A21208,
    anti-mouse
    suggested: (Molecular Probes Cat# A-21202, RRID:AB_141607)
    anti-Rat
    suggested: (Molecular Probes Cat# A-21208, RRID:AB_141709)
    Experimental Models: Organisms/Strains
    SentencesResources
    Animal infection experiments were conducted using wildtype C57BL/6J mice, Syrian golden hamsters (HsdHan®: AURA, Envigo, Haslett MI), and hACE2 mice (B6.Cg-Tg(K18-ACE2)2Prlmn/J, JAX, Bar Harbor, Maine).
    C57BL/6J
    suggested: None
    B6.Cg-Tg(K18-ACE2)2Prlmn/J
    suggested: RRID:IMSR_JAX:034860)
    Software and Algorithms
    SentencesResources
    Images were cut by Photoshop and assembled by Illustrator.
    Photoshop
    suggested: (Adobe Photoshop, RRID:SCR_014199)
    Illustrator
    suggested: (Adobe Illustrator, RRID:SCR_010279)
    The Seurat R package was used for subsequent analysis.
    Seurat
    suggested: (SEURAT, RRID:SCR_007322)
    Data analyses were carried out using GraphPad Prism.
    GraphPad Prism
    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: 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.

    Results from scite Reference Check: We found no unreliable references.

    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 10.1101/2022.04.12.487379 on bioRxiv