Hyperinflammatory environment drives dysfunctional myeloid cell effector response to bacterial challenge in COVID-19

  1. Srikanth Mairpady Shambat
  2. Alejandro Gómez-Mejia
  3. Tiziano A. Schweizer
  4. Markus Huemer
  5. Chun-Chi Chang
  6. Claudio Acevedo
  7. Judith Bergada-Pijuan
  8. Clément Vulin
  9. Daniel A. Hofmaenner
  10. Thomas C. Scheier
  11. Sanne Hertegonne
  12. Elena Parietti
  13. Nataliya Miroshnikova
  14. Pedro D. Wendel Garcia
  15. Matthias P. Hilty
  16. Philipp Karl Buehler
  17. Reto A. Schuepbach
  18. Silvio D. Brugger
  19. Annelies S. Zinkernagel

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Abstract

COVID-19 displays diverse disease severities and symptoms including acute systemic inflammation and hypercytokinemia, with subsequent dysregulation of immune cells. Bacterial superinfections in COVID-19 can further complicate the disease course and are associated with increased mortality. However, there is limited understanding of how SARS-CoV-2 pathogenesis and hypercytokinemia impede the innate immune function against bacterial superinfections. We assessed the influence of COVID-19 plasma hypercytokinemia on the functional responses of myeloid immune cells upon bacterial challenges from acute-phase COVID-19 patients and their corresponding recovery-phase. We show that a severe hypercytokinemia status in COVID-19 patients correlates with the development of bacterial superinfections. Neutrophils and monocytes derived from COVID-19 patients in their acute-phase showed an impaired intracellular microbicidal capacity upon bacterial challenges. The impaired microbicidal capacity was reflected by abrogated MPO and reduced NETs production in neutrophils along with reduced ROS production in both neutrophils and monocytes. Moreover, we observed a distinct pattern of cell surface receptor expression on both neutrophils and monocytes, in line with suppressed autocrine and paracrine cytokine signaling. This phenotype was characterized by a high expression of CD66b, CXCR4 and low expression of CXCR1, CXCR2 and CD15 in neutrophils and low expression of HLA-DR, CD86 and high expression of CD163 and CD11b in monocytes. Furthermore, the impaired antibacterial effector function was mediated by synergistic effect of the cytokines TNF-α, IFN-γ and IL-4. COVID-19 patients receiving dexamethasone showed a significant reduction of overall inflammatory markers in the plasma as well as exhibited an enhanced immune response towards bacterial challenge ex vivo . Finally, broad anti-inflammatory treatment was associated with a reduction in CRP, IL-6 levels as well as length of ICU stay and ventilation-days in critically ill COVID-19 patients. Our data provides insights into the transient functional dysregulation of myeloid immune cells against subsequent bacterial infections in COVID-19 patients and describe a beneficial role for the use of dexamethasone in these patients.

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  1. Version published to 10.1371/journal.ppat.1010176
  2. ScreenIT

    SciScore for 10.1101/2020.12.01.406306: (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 local ethics committee of the Canton of Zurich, Switzerland (Kantonale Ethikkommission Zurich BASEC ID 2020 - 00646).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Antibodies included anti-CD15 eFluor450 (clone: HI98), anti-CD181 FITC (8F1-1-4), anti-CD182 PerCP-eFluor710 (5E8-C7-F10), anti-CD183 PE-eFluor610 (CEW33D), anti-CD66b APC (G10F5), anti-HLA-DR eFluor450 (LN3), anti-CD45 eFluor506 (HI30)
    anti-CD15
    suggested: (Thermo Fisher Scientific Cat# MA1-42216, RRID:AB_2537341)
    anti-CD181 FITC
    suggested: (Thermo Fisher Scientific Cat# 11-1819-42, RRID:AB_11218880)
    anti-CD182
    suggested: None
    anti-CD183 PE-eFluor610
    suggested: None
    anti-CD66b APC
    suggested: (Thermo Fisher Scientific Cat# 17-0666-41, RRID:AB_2573151)
    anti-HLA-DR
    suggested: None
    anti-CD45
    suggested: None
    HI30
    suggested: None
    Software and Algorithms
    SentencesResources
    Flow cytometry data were analyzed with FlowJo (v10.2).
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    The obtained images were processed using Imaris 9.2.0 software (Bitplane) to obtain tifs for further analysis.
    Imaris
    suggested: (Imaris, RRID:SCR_007370)
    Images were processed using ImageJ software (Rasband, W.S., ImageJ, U. S. National Institutes of Health, Bethesda, Maryland, USA, https://imagej.nih.gov/ij/, 1997-2018) and Matlab R2020a (MathWorks).
    ImageJ
    suggested: (ImageJ, RRID:SCR_003070)
    Matlab
    suggested: (MATLAB, RRID:SCR_001622)
    Kruskal-Wallis test with Dunn’s multiple comparisons test was used to evaluate differences among the three groups in all the analyses (GraphPad).
    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: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04410263RecruitingMicrobiota in COVID-19 Patients for Future Therapeutic and P…

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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.
    • Thank you for including a protocol registration statement.

    About SciScore

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  3. Version published to 10.1101/2020.12.01.406306v1 on bioRxiv