Opposing roles for sMAdCAM and IL-15 in COVID-19 associated cellular immune pathology

  1. Amit Kumar Singh
  2. Nandini Kasarpalkar
  3. Shilpa Bhowmick
  4. Gaurav Paradkar
  5. Mayur Talreja
  6. Karan Shah
  7. Abhishek Tiwari
  8. Harsha Palav
  9. Snehal Kaginkar
  10. Rajiv Kulkarni
  11. Ashwini Patil
  12. Varsha Kalsurkar
  13. Sachee Agrawal
  14. Jayanthi Shastri
  15. Rajesh Dere
  16. Ramesh Bharmal
  17. Smita D Mahale
  18. Vikrant M Bhor
  19. Vainav Patel

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Abstract

Immune cell dysregulation and lymphopenia characterize COVID-19 pathology in moderate to severe disease. While underlying inflammatory factors have been extensively studied, homeostatic and mucosal migratory signatures remain largely unexplored as causative factors. In this study, we evaluated the association of circulating IL-6, soluble mucosal addressin cell adhesion molecule (sMAdCAM), and IL-15 with cellular dysfunction characterizing mild and hypoxemic stages of COVID-19. A cohort of SARS-CoV-2 infected individuals (n = 130) at various stages of disease progression together with healthy controls (n = 16) were recruited from COVID Care Centres (CCCs) across Mumbai, India. Multiparametric flow cytometry was used to perform in-depth immune subset characterization and to measure plasma IL-6 levels. sMAdCAM, IL-15 levels were quantified using ELISA. Distinct depletion profiles, with relative sparing of CD8 effector memory and CD4+ regulatory T cells, were observed in hypoxemic disease within the lymphocyte compartment. An apparent increase in the frequency of intermediate monocytes characterized both mild as well as hypoxemic disease. IL-6 levels inversely correlated with those of sMAdCAM and both markers showed converse associations with observed lympho-depletion suggesting opposing roles in pathogenesis. Interestingly, IL-15, a key cytokine involved in lymphocyte activation and homeostasis, was detected in symptomatic individuals but not in healthy controls or asymptomatic cases. Further, plasma IL-15 levels negatively correlated with T, B, and NK count suggesting a compensatory production of this cytokine in response to the profound lymphopenia. Finally, higher levels of plasma IL-15 and IL-6, but not sMAdCAM, were associated with a longer duration of hospitalization.

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  1. Version published to 10.1002/jlb.3covbcr0621-300r
  2. ScreenIT

    SciScore for 10.1101/2021.03.25.21254215: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: Study population, setting, and data collection: Sixteen seronegative controls and a total of 125 in-patients individuals were recruited, following informed consent, for the study from the COVID Care Centres associated with BYL Nair hospital and T N medical college, Municipal Corporation of Greater Mumbai (MCGM), Mumbai following approval of institutional ethics committees.
    IRB: Study population, setting, and data collection: Sixteen seronegative controls and a total of 125 in-patients individuals were recruited, following informed consent, for the study from the COVID Care Centres associated with BYL Nair hospital and T N medical college, Municipal Corporation of Greater Mumbai (MCGM), Mumbai following approval of institutional ethics committees.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    IgG and IgM antibodies against SARS-CoV-2 were detected in fresh plasma samples using Rapid test from Voxpress (Voxtur Bio LTD, India) and Chemiluminescence immunoassay (CLIA) directed against SARS-CoV-2 anti-NC IgG.
    SARS-CoV-2
    suggested: None
    anti-NC IgG
    suggested: None
    Data analysis was carried out using FlowJo software (BD biosciences) Immunophenotyping: For phenotypic characterization, immunostaining of 200 μl of fresh peripheral whole blood with following fluorescently labelled monoclonal antibodies, anti-CD3 (Clone:SK7), anti-CD4 (Clone: RPA-T4)
    anti-CD3
    suggested: None
    anti-CD4
    suggested: None
    Software and Algorithms
    SentencesResources
    Data analysis was carried out using FlowJo software (BD biosciences) Immunophenotyping: For phenotypic characterization, immunostaining of 200 μl of fresh peripheral whole blood with following fluorescently labelled monoclonal antibodies, anti-CD3 (Clone:SK7), anti-CD4 (Clone: RPA-T4)
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Statistics: Statistical analysis was performed in GraphPad Prism 8 using non parametric tests.
    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.

    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 10.1101/2021.03.25.21254215v1 on medRxiv