Comorbid illnesses are associated with altered adaptive immune responses to SARS-CoV-2

  1. Krystle K.Q. Yu
  2. Stephanie Fischinger
  3. Malisa T. Smith
  4. Caroline Atyeo
  5. Deniz Cizmeci
  6. Caitlin R. Wolf
  7. Erik D. Layton
  8. Jennifer K. Logue
  9. Melissa S. Aguilar
  10. Kiel Shuey
  11. Carolin Loos
  12. Jingyou Yu
  13. Nicholas Franko
  14. Robert Y. Choi
  15. Anna Wald
  16. Dan H. Barouch
  17. David M. Koelle
  18. Douglas Lauffenburger
  19. Helen Y. Chu
  20. Galit Alter
  21. Chetan Seshadri

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Abstract

Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multiparameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized ( n = 20) or not hospitalized ( n = 40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4 + T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4 + T cells and antibodies targeting the S1 domain of spike among subjects who were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2, which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19.

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  1. Version published to 10.1172/jci.insight.146242
  2. ScreenIT

    SciScore for 10.1101/2020.11.25.20235150: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Study Approval: The studies were approved by the University of Washington Human Subjects Institutional Review Board, and all participants, or their legally authorized representatives, completed informed consent.
    Consent: Study Approval: The studies were approved by the University of Washington Human Subjects Institutional Review Board, and all participants, or their legally authorized representatives, completed informed consent.
    Randomizationnot detected.
    BlindingAll experiments were performed in duplicate while operators were blinded to study group assignment, and all cases and controls were run at the same time to avoid batch effects.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Antibody titer measurements and FcR binding: In order to measure antigen-specific antibody subclass, isotype, and Fc-receptor (FcR) binding levels, a customized multiplexed Luminex assay was utilized, as previously described(57).
    antigen-specific antibody subclass , isotype ,
    suggested: None
    Antigen-specific antibody titers were detected with Phycoerythrin (PE)-coupled antibodies against IgG1, IgG2, IgG3, IgG4, IgA, and IgM (SouthernBiotech, Birmingham, AL).
    Phycoerythrin ( PE)-coupled antibodies against IgG1
    suggested: None
    IgG1
    suggested: None
    IgG2
    suggested: None
    IgG3
    suggested: None
    IgG4
    suggested: None
    IgA
    suggested: None
    IgM ( SouthernBiotech , Birmingham , AL)
    suggested: None
    IgM
    suggested: None
    Functional antibody measurements: Bead-based assays were used to quantify antibody-dependent cellular phagocytosis (ADCP), antibody-dependent neutrophil phagocytosis (ADNP), and antibody-dependent complement deposition (ADCD), as previously described (58–60).
    antibody-dependent neutrophil phagocytosis ( ADNP) ,
    suggested: None
    antibody-dependent complement deposition ( ADCD)
    suggested: None
    Then, a PacBlue anti-CD66b detection antibody (clone G10F5) (RUO) (BioLegend, San Diego, CA) was used to stain neutrophils.
    anti-CD66b
    suggested: None
    anti-CD56 PE-Cy7 (clone B159), and anti-CD3 PacBlue (clone SP34-2) antibodies (BD Biosciences, San Jose, CA).
    PE-Cy7
    suggested: (BD Biosciences Cat# 557749, RRID:AB_396855)
    anti-CD3
    suggested: None
    Antibodies included anti-CD3 ECD (clone UCHT1) (Beckman Coulter, Brea, CA)
    anti-CD3 ECD
    suggested: None
    A preparation of anti-CCR7 BV711 antibody (clone 150503) (BD Biosciences, San Jose, CA) in FACS buffer was centrifuged at 10,000xg for 5 minutes and then added to the cells for 30 minutes at 37°C.
    anti-CCR7 BV711
    suggested: (BD Biosciences Cat# 566752, RRID:AB_2869849)
    Experimental Models: Cell Lines
    SentencesResources
    luciferase reporter plasmid pLenti-CMV Puro-Luc (Addgene, Watertown, MA), and spike protein expressing pcDNA3.1-SARS CoV-2 SΔCT were co-transfected into HEK293T cells by lipofectamine 2,000 (Thermo Fisher Scientific, Waltham, MA).
    HEK293T
    suggested: NCBI_Iran Cat# C498, RRID:CVCL_0063)
    The mixture was incubated at 37°C for 1 hour before adding to HEK293T-hACE2 cells.
    HEK293T-hACE2
    suggested: None
    For measuring monocyte phagocytosis, 2.5×104 THP-1 cells (ATCC, Manassas, VA) were added per well and incubated for 16 hours at 37°C.
    THP-1
    suggested: None
    Software and Algorithms
    SentencesResources
    The supernatant was decanted, and the viable cells were enumerated using the Guava easyCyte (MilliporeSigma, Burlington, MA) with guavaSoft 2.6 software.
    guavaSoft
    suggested: None

    Results from OddPub: Thank you for sharing your data.

    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
    NCT04338360Approved for marketingExpanded Access to Convalescent Plasma for the Treatment of …

    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 10.1101/2020.11.25.20235150 on medRxiv