The Delta variant of SARS-CoV-2 maintains high sensitivity to interferons in human lung cells

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Interferons are a major part of the anti-viral innate defense system. Successful pathogens, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), need to overcome these defenses to establish an infection. Early induction of interferons (IFNs) protects against severe coronavirus disease 2019 (COVID-19). In line with this, SARS-CoV-2 is inhibited by IFNs in vitro , and IFN-based therapies against COVID-19 are investigated in clinical trials. However, SARS-CoV-2 continues to adapt to the human population resulting in the emergence of variants characterized by increased transmission fitness and/or decreased sensitivity to preventive or therapeutic measures. It has been suggested that the efficient spread of these so-called “Variants of Concern” (VOCs) may also involve reduced sensitivity to IFNs. Here, we examined whether the four current VOCs (Alpha, Beta, Gamma and Delta) differ in replication efficiency or IFN sensitivity from an early isolate of SARS-CoV-2. All viruses replicated in a human lung cell line and in iPSC-derived alveolar type II cells (iAT2). The Delta variant showed accelerated replication kinetics and higher infectious virus production compared to the early 2020 isolate. Replication of all SARS-CoV-2 VOCs was reduced in the presence of exogenous type I, II and III IFNs. On average, the Alpha variant was the least susceptible to IFNs and the Alpha, Beta and Gamma variants show increased resistance against type III IFN. Although the Delta variant has outcompeted all other variants in humans it remained as sensitive to IFNs as an early 2020 SARS-CoV-2 isolate. This suggests that increased replication fitness rather than IFN resistance may be a reason for its dominance. Our results may help to understand changes in innate immune susceptibility of VOCs, and inform clinical trials exploring IFN-based COVID-19 therapies.

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  1. SciScore for 10.1101/2021.11.16.468777: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    RandomizationFirst, 1 µl random hexamers (50 ng/µl), 1 µl dNTPs mix (10 mM each), and 11 µl template RNA (diluted 1:10 in DNase/RNase free water) were mixed, incubated at 65°C for 5 min and placed on ice for 1 min.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    Vero E6 cells (Cercopithecus aethiops derived epithelial kidney, ATCC) and TMPRSS2-expressing Vero E6 cells (kindly provided by the National Institute for Biological Standards and Control (NIBSC), No. 100978) were grown in Dulbecco’s modified Eagle’s medium (DMEM, Gibco, Cat#41965039) supplemented with 2.5% (upon and after viral infection) or 10% (during all other times) heat-inactivated FBS (Gibco, Cat#10270106), 100 units/ml penicillin, 100 µg/ml streptomycin (ThermoFisher, Cat#15140122), 2 mM L-glutamine (Gibco, Cat#25030081), 1 mM sodium pyruvate (Pan Biotech, Cat# P04-8010), 1x non-essential amino acids (Sigma, Cat#M7145) and 1 mg/mL Geneticin (Gibco, Cat#10131-019) (for TMPRSS2-expressing Vero E6 cells).
    Vero E6
    suggested: RRID:CVCL_XD71)
    Caco-2 cells (human epithelial colorectal adenocarcinoma, kindly provided by Prof. Holger Barth (Ulm University)) were grown in the same media as Vero E6 cells but with supplementation of 10% heat-inactivated FBS.
    suggested: None
    24 h post-seeding, Calu-3 cells were infected with the different variants of SARS-CoV-2 (MOI 0.05).
    suggested: BCRJ Cat# 0264, RRID:CVCL_0609)
    Software and Algorithms
    The obtained sequenced reads were demultiplexed and mapped against the SARS-CoV-2 reference genome (NC_045512.2) with BWA-MEM[36].
    suggested: None
    The mapped reads and the pileup file were used to construct the consensus sequence with the iVar package[38] using default settings.
    suggested: None

    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 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.
    • No protocol registration statement was detected.

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

    About SciScore

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