Cellular events of acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates

  1. M. D. Fahlberg
  2. R. V. Blair
  3. L. A. Doyle-Meyers
  4. C. C. Midkiff
  5. G. Zenere
  6. K. E. Russell-Lodrigue
  7. C. J. Monjure
  8. E. H. Haupt
  9. T. P. Penney
  10. G. Lehmicke
  11. B. M. Threeton
  12. N. Golden
  13. P. K. Datta
  14. C. J. Roy
  15. R. P. Bohm
  16. N. J. Maness
  17. T. Fischer
  18. J. Rappaport
  19. M. Vaccari

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Abstract

Understanding SARS-CoV-2 associated immune pathology is crucial to develop pan-effective vaccines and treatments. Here we investigate the immune events from the acute state up to four weeks post SARS-CoV-2 infection, in non-human primates (NHP) with heterogeneous pulmonary pathology. We show a robust migration of CD16 expressing monocytes to the lungs occurring during the acute phase, and we describe two subsets of interstitial macrophages (HLA-DR + CD206 − ): a transitional CD11c + CD16 + cell population directly associated with IL-6 levels in plasma, and a long-lasting CD11b + CD16 + cell population. Trafficking of monocytes is mediated by TARC (CCL17) and associates with viral load measured in bronchial brushes. We also describe associations between disease outcomes and high levels of cell infiltration in lungs including CD11b + CD16 hi macrophages and CD11b + neutrophils. Accumulation of macrophages is long-lasting and detectable even in animals with mild or no signs of disease. Interestingly, animals with anti-inflammatory responses including high IL-10:IL-6 and kynurenine to tryptophan ratios show less severe illness. Our results unravel cellular mechanisms of COVID-19 and suggest that NHP may be appropriate models to test immune therapies.

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  1. Version published to 10.1038/s41467-020-19967-4
  2. ScreenIT

    SciScore for 10.1101/2020.07.21.213777: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIACUC: The Institutional Animal Care and Use Committee of Tulane University reviewed and approved all the procedures for this study.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableThe multi route exposure was given to four animals, one adult RM male (GH99, 14 years old), one adult RM female (HD09, 13 years old) and two AGM, one aged male (NC40, 16 years old, approximately) and one aged female (NC33, 16 years old, approximately).
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    BAL and PBMCs staining: Freshly obtained PBMCs and cells obtained from BAL were stained with appropriate antibody cocktails and incubated for 30 minutes at room temperature.
    BAL
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    The virus stock was prepared in Vero E6 cells and the sequence confirmed by PCR and/or Sanger sequencing.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Software and Algorithms
    SentencesResources
    The African green monkeys were wild caught and at the TNPRC for over a year before being assigned to this study.
    TNPRC
    suggested: None
    tSNE analyses were performed in FlowJo using the opt-SNE algorithm and plots were created in R using the ggplot2 package59.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)
    All statistical analyses were performed using GraphPad Prism (version 8.4.2 GraphPad Software, La Jolla California USA) and R software (URL http://www.R-project.org/).
    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 38 and 39. 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.
    • 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

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  3. Version published to 10.1101/2020.07.21.213777 on bioRxiv