SARS-CoV-2 Variant Delta Potently Suppresses Innate Immune Response and Evades Interferon-Activated Antiviral Responses

  1. Dixit Tandel
  2. Vishal Sah
  3. Nitesh Kumar Singh
  4. Poojitha Sai Potharaju
  5. Divya Gupta
  6. Sauhard Shrivastava
  7. Divya Tej Sowpati
  8. Krishnan H Harshan

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Abstract

Delta variant of SARS-CoV-2 has caused more severe infections than its previous variants. We studied the host innate immune response to Delta, Alpha and two earlier variants to map the evolution of the recent ones. Our biochemical and transcriptomic studies reveal that Alpha and Delta have progressively evolved over the ancestral variants by silencing innate immune response, thereby limiting cytokine and chemokine production. Though Alpha silenced RLR pathway just as Delta, it failed to persistently silence the innate immune response unlike Delta. Both Alpha and Delta have evolved to resist IFN treatment while they are still susceptible to RLR activation, further highlighting the importance of RLR-mediated, IFN-independent mechanisms in restricting SARS-CoV-2. Our studies reveal that SARS-CoV-2 Delta has integrated multiple mechanisms to silence host innate immune response and evade IFN response. Delta’s silent replication and sustained suppression of host innate immune response, possibly resulting in delayed or reduced intervention by the adaptive immune response, could potentially contribute to the severe symptoms and poor recovery index associated with it.

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  1. ScreenIT

    SciScore for 10.1101/2022.02.22.481430: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: Institutional ethics clearance: Institutional ethics clearance (IEC-82/2020) was obtained for the patient sample processing for virus culture.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Antibodies and immunoblotting: All primary antibodies were purchased from Cell Signaling Technologies except the anti-Spike antibody (Novus Biologicals), and anti-Nucleocapsid, anti-Tubulin and anti-GAPDH (Thermo Fisher) antibodies.
    anti-Spike
    suggested: None
    anti-Nucleocapsid ,
    suggested: None
    anti-Tubulin
    suggested: None
    anti-GAPDH
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Caco2, purchased from ATCC, were grown similarly, but supplemented with 20% FBS.
    Caco2
    suggested: None
    The viral supernatants were serially diluted to prepare inocula that were inoculated on cultured Vero cells.
    Vero
    suggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)
    Software and Algorithms
    SentencesResources
    Quantification was performed using ImageJ.
    ImageJ
    suggested: (ImageJ, RRID:SCR_003070)
    The processed reads were then mapped to the human genome GRCh38 using Hisat2 with default parameters (39).
    Hisat2
    suggested: (HISAT2, RRID:SCR_015530)
    Differential gene expression analysis was performed using DESeq2 (42).
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)
    Functional enrichment analysis: Functional enrichment analysis was performed using clusterProfiler (43) for GO term and KEGG pathways enrichment.
    KEGG
    suggested: (KEGG, RRID:SCR_012773)
    Similar enriched terms were further merged using the ‘simplify’ function of clusterProfiler with similarity cut-off set to 0.7.
    clusterProfiler
    suggested: (clusterProfiler, RRID:SCR_016884)
    All graphs were prepared using GraphPad Prism version 8.0.2.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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: 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.

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

    About SciScore

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  2. Version published to 10.1101/2022.02.22.481430v1 on bioRxiv