Dysregulation of brain and choroid plexus cell types in severe COVID-19

  1. Andrew C. Yang
  2. Fabian Kern
  3. Patricia M. Losada
  4. Maayan R. Agam
  5. Christina A. Maat
  6. Georges P. Schmartz
  7. Tobias Fehlmann
  8. Julian A. Stein
  9. Nicholas Schaum
  10. Davis P. Lee
  11. Kruti Calcuttawala
  12. Ryan T. Vest
  13. Daniela Berdnik
  14. Nannan Lu
  15. Oliver Hahn
  16. David Gate
  17. M. Windy McNerney
  18. Divya Channappa
  19. Inma Cobos
  20. Nicole Ludwig
  21. Walter J. Schulz-Schaeffer
  22. Andreas Keller
  23. Tony Wyss-Coray

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Abstract

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  1. Version published to 10.1038/s41586-021-03710-0
  2. ScreenIT

    SciScore for 10.1101/2020.10.22.349415: (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

    Antibodies
    SentencesResources
    Following antigen retrieval, sections were incubated for 45 minutes at room temperature with the anti-SARS spike glycoprotein antibody 3A2 (rabbit, Abcam ab272420 1:100 diluted in Dako REAL antibody diluent #S2022), which has been validated in previous publications20,41.
    anti-SARS spike glycoprotein
    suggested: (MBL International Cat# RK-65-102, RRID:AB_1279268)
    Software and Algorithms
    SentencesResources
    Biological pathway and gene ontology enrichment analysis was performed using Enrichr155, Metascape156, or GeneTrail 3157 with input species set to Homo sapiens156 and using standard parameters.
    GeneTrail
    suggested: (GeneTrail, RRID:SCR_006250)
    Markers were defined based on the MAST algorithm using only positive values with Log (fold change) > 0.25 (absolute value), adjusted P value (Bonferroni correction) < 0.01.
    MAST
    suggested: (MAST, RRID:SCR_016340)
    We also adopted a complementary approach161 focusing on SARS-CoV-2 reads, whereby barcoded but unmapped BAM reads were aligned using STAR to the SARS-CoV-2 reference genome, with a less stringent mapping parameter (outFilterMatchNmin 25-30) than the original Viral-Track pipeline.
    STAR
    suggested: (STAR, RRID:SCR_015899)
    Overall in-silico analysis: Analysis and dissection of the data was performed using the statistical programming language R (v.3.6.3) using the following general-purpose package for loading, saving, and manipulating data, as well as generating plots, and fitting statistical models: dplyr (v.1.0.0), ggplot2 (v.3.2.2.), patchwork (v.1.0.1), openxlsx (v.4.1.5), bioconductor-scater (v.1.14.6), bioconductor-dropletutils (v1.6.1), bioconductor-complexheatmap (v.2.2.0), tidyverse (v.1.3.0), and lsa (v.0.73.2).
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    There are, however, limitations to consider given the unique logistical circumstances of a pandemic. With most postmortem COVID-19 brain tissue immediately fixed42 or not handled with snRNA-seq studies in mind for safety and regulatory reasons, there is a lack of the high-quality tissue necessary for such studies21,23,24. This has precluded larger study cohorts that could be more representative of COVID-19 patients as a whole. For example, while we and a recent IHC-based study of 43 patient brains5 (the largest to date) do not find a clear correlation between detectable brain SARS-CoV-2 and glial inflammation or neurological symptoms, this may not be representative of all patients, especially those without pre-existing co-morbidities or who do not require ventilation136. Furthermore, the associations with chronic CNS disease may not be relevant in mild COVID-19 disease and may change over time in severe COVID-19 survivors. Long-term postmortem studies of survivors after the acute phase of disease are not currently possible to assess this. However, there is precedent for acute viral infections causing long-term inflammation and dysfunction predisposing neurodegenerative disease137–140. Understanding the underlying mechanisms of how SARS-CoV-2 affects the brain may inform therapeutic approaches121. Most molecular studies to date on SARS-CoV-2 neurotropism have made powerful use of cultured organoids, though they have reached conflicting conclusions21–26. Here, in postmortem COV...

    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.

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  3. Version published to 10.1101/2020.10.22.349415v1 on bioRxiv