Low baseline pulmonary levels of cytotoxic lymphocytes as a predisposing risk factor for severe COVID-19

  1. Pascal H.G. Duijf

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Abstract

COVID-19 is caused by the coronavirus SARS-CoV-2 and currently has detrimental human health, community and economic impacts around the world. It is unclear why some SARS-CoV-2-positive individuals remain asymptomatic, while others develop severe symptoms. Baseline pulmonary levels of anti-viral leukocytes, already residing in the lung prior to infection, may orchestrate an effective early immune response and prevent severe symptoms. Using “ in silico flow cytometry”, we deconvoluted the levels of all seven types of anti-viral leukocytes in 1,927 human lung tissues. Baseline levels of CD8+ T cells, resting NK cells and activated NK cells, as well as cytokines that recruit these, are significantly lower in lung tissues with high expression of the SARS-CoV-2 entry receptor ACE2. We observe this in univariate analyses, in multivariate analyses, and in two independent datasets. Relevantly, ACE2 mRNA and protein levels very strongly correlate in human cells and tissues. Above findings also largely apply to the SARS-CoV-2 entry protease TMPRSS2. Both SARS-CoV-2-infected lung cells and COVID-19 lung tissues show upregulation of CD8+ T cell- and NK cell-recruiting cytokines. Moreover, tissue-resident CD8+ T cells and inflammatory NK cells are significantly more abundant in bronchoalveolar lavages from mildly affected COVID-19 patients, compared to severe cases. This suggests that these lymphocytes are important for preventing severe symptoms. Elevated ACE2 expression increases sensitivity to coronavirus infection. Thus, our results suggest that some individuals may be exceedingly susceptible to develop severe COVID-19 due to concomitant high pre-existing ACE2 and TMPRSS expression and low baseline cytotoxic lymphocyte levels in the lung.

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  1. ScreenIT

    SciScore for 10.1101/2020.05.04.075291: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    These were based on immunohistochemical staining of the tissues using DAB (3,3’-diaminobenzidine)-labeled antibodies (HPA000288, CAB026174), followed by knowledge-based annotation, as described on said website.
    CAB026174
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    These represent fold increase in expression in Calu-3 lung cells, 24 hours after infection with SARS-CoV-2 at a multiplicity of infection of 2, compared to uninfected Calu-3 cells.
    Calu-3
    suggested: KCLB Cat# 30055, RRID:CVCL_0609)
    Software and Algorithms
    SentencesResources
    Gene expression levels were obtained using RNA-SeQC v1.1.9 (51) and expressed in transcripts per million (TPM).
    RNA-SeQC
    suggested: (RNA-SeQC, RRID:SCR_005120)
    This dataset was accessed via Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo), accession number GSE23546, and was previously described (52).
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    All analyses were performed in the R computing environment (R Project for Statistical Computing, Vienna, Austria).
    R Project for Statistical
    suggested: (R Project for Statistical Computing, RRID:SCR_001905)
    First, mRNA expression levels from 40 human tissues were obtained from the Human Protein Atlas (https://www.proteinatlas.org).
    https://www.proteinatlas.org
    suggested: (HPA, RRID:SCR_006710)

    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

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  2. Version published to 10.1101/2020.05.04.075291 on bioRxiv