Signatures of mast cell activation are associated with severe COVID-19

  1. Janessa Tan
  2. Danielle E. Anderson
  3. Abhay P. S. Rathore
  4. Aled O’Neill
  5. Chinmay Kumar Mantri
  6. Wilfried A. A. Saron
  7. Cheryl Lee
  8. Chu Wern Cui
  9. Adrian E. Z. Kang
  10. Randy Foo
  11. Shirin Kalimuddin
  12. Jenny G. Low
  13. Lena Ho
  14. Paul Tambyah
  15. Thomas W. Burke
  16. Christopher W. Woods
  17. Kuan Rong Chan
  18. Jörn Karhausen
  19. Ashley L. St. John

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Abstract

Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in severely ill patients and the pathophysiology of disease is thought to be immune-mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond to certain viruses and allergens, often promoting inflammation. We observed widespread degranulation of MCs during acute and unresolved airway inflammation in SARS-CoV-2-infected mice and non-human primates. In humans, transcriptional changes in patients requiring oxygen supplementation also implicated cells with a MC phenotype. MC activation in humans was confirmed, through detection of the MC-specific protease, chymase, levels of which were significantly correlated with disease severity. These results support the association of MC activation with severe COVID-19, suggesting potential strategies for intervention.

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    SciScore for 10.1101/2021.05.31.21255594: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: Study approvals: All mouse and primate studies were approved by the SingHealth Institutional Animal Care and Use Committee of the SingHealth Experimental Medicine Centre (SEMC).
    IRB: The data associated with human transcriptional responses was approved by the SingHealth Combined Institutional Review Board (CIRB 2017/2374).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    A limitation here is the potential to only monitor transcriptional responses in the human blood, yet, our animal model data supports that there is expansion of MCs in the lung tissue as well. This is consistent with the observation in a murine model of H1N1 influenza infection where recruitment and maturation of MC progenitors in the lung was suggested to occur approximately 2 weeks after the infection(34). We also noted an unusually high density of MCs in damaged and hemorrhagic regions NHP lungs at 3 weeks post SARS-CoV-2 infection. Increased transcriptional upregulation of the chemokine CXCR2 in the blood of severe COVID human patients is also suggestive of MC precursor migration into lung, as was seen in the context of other diseases(42). Similarly, other studies have identified transcriptional signatures of granulocyte activation as well as increases in cells such as neutrophils, eosinophils and basophils and T cells in the blood or lung tissue itself in severe COVID-19(1, 6-8). As tissue-resident cells, MCs are considered sentinels and they can promote the trafficking of many of these cell types into tissues during both allergic and infection-induced inflammation(9, 12, 43). Aside from the lung-associated pathologies of COVID-19, some individuals also experience other hematological changes and cardiovascular events, including intra-vascular coagulation, endothelial damage with ischemic complications, the development of rashes that could be accentuated by damaged microva...

    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 page 15. 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.

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

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  2. Version published to 10.1101/2021.05.31.21255594v1 on medRxiv