SARS-CoV-2 Variant Delta Potently Suppresses Innate Immune Response and Evades Interferon-Activated Antiviral Responses
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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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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
Ethics IACUC: Institutional ethics clearance: Institutional ethics clearance (IEC-82/2020) was obtained for the patient sample processing for virus culture. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources 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-Spikesuggested: Noneanti-Nucleocapsid ,suggested: Noneanti-Tubulinsuggested: Noneanti-GAPDHsuggested: None… 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
Ethics IACUC: Institutional ethics clearance: Institutional ethics clearance (IEC-82/2020) was obtained for the patient sample processing for virus culture. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources 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-Spikesuggested: Noneanti-Nucleocapsid ,suggested: Noneanti-Tubulinsuggested: Noneanti-GAPDHsuggested: NoneExperimental Models: Cell Lines Sentences Resources Caco2, purchased from ATCC, were grown similarly, but supplemented with 20% FBS. Caco2suggested: NoneThe viral supernatants were serially diluted to prepare inocula that were inoculated on cultured Vero cells. Verosuggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)Software and Algorithms Sentences Resources Quantification was performed using ImageJ. ImageJsuggested: (ImageJ, RRID:SCR_003070)The processed reads were then mapped to the human genome GRCh38 using Hisat2 with default parameters (39). Hisat2suggested: (HISAT2, RRID:SCR_015530)Differential gene expression analysis was performed using DESeq2 (42). DESeq2suggested: (DESeq, RRID:SCR_000154)Functional enrichment analysis: Functional enrichment analysis was performed using clusterProfiler (43) for GO term and KEGG pathways enrichment. KEGGsuggested: (KEGG, RRID:SCR_012773)Similar enriched terms were further merged using the ‘simplify’ function of clusterProfiler with similarity cut-off set to 0.7. clusterProfilersuggested: (clusterProfiler, RRID:SCR_016884)All graphs were prepared using GraphPad Prism version 8.0.2. GraphPad Prismsuggested: (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.
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