MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells

Yin, Xin; Riva, Laura; Pu, Yuan; Martin-Sancho, Laura; Kanamune, Jun; Yamamoto, Yuki; Sakai, Kouji; Gotoh, Shimpei; Miorin, Lisa; Jesus, Paul D. De; Yang, Ching‐Chieh; Herbert, Kristina M.; Yoh, Sunnie M.; Hultquist, Judd F.; Garcı́a-Sastre, Adolfo; Chanda, Sumit K.

doi:10.1016/j.celrep.2020.108628

Cited by 335 publications

(313 citation statements)

References 65 publications

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“…Both MDA5 and RIG-I may displace viral proteins pre-bound to dsRNA in a manner dependent on their ATP hydrolysis, thus exerting a MAVS-IFN-independent broad-spectrum antiviral role (Sindbis, yellow fever, Coxsackie B, Sendai, influenza A, and human parainfluenza 3 viruses) 18 . During the submission of this manuscript, a study showed an important anti-SARS-CoV-2 role of MDA5 that is consistent with our results, however dispensable function of RIG-I in limiting SARS-CoV-2 infection 19 . This discrepancy could be due to a difference in the cell line and gene knockout method.…”

Section: Resultssupporting

confidence: 90%

Differential roles of RIG-I-like receptors in SARS-CoV-2 infection

Yang

Geng

Harrison

et al. 2021

Preprint

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The retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) are the major viral RNA sensors that are essential for activation of antiviral immune responses. However, their roles in severe acute respiratory syndrome (SARS)-causing coronavirus (CoV) infection are largely unknown. Herein we investigate their functions in human epithelial cells, the primary and initial target of SARS-CoV-2, and the first line of host defense. A deficiency in MDA5 (MDA5-/-), RIG-I or mitochondrial antiviral signaling protein (MAVS) greatly enhanced viral replication. Expression of the type I/III interferons (IFN) was upregulated following infection in wild-type cells, while this upregulation was severely abolished in MDA5-/- and MAVS-/-, but not in RIG-I-/- cells. Of note, ACE2 expression was ~2.5 fold higher in RIG-I-/- than WT cells. These data demonstrate a dominant role of MDA5 in activating the type I/III IFN response to SARS-CoV-2, and an IFN-independent anti-SARS-CoV-2 role of RIG-I.

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Section: Resultssupporting

confidence: 90%

Differential roles of RIG-I-like receptors in SARS-CoV-2 infection

Yang

Geng

Harrison

et al. 2021

Preprint

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“…We also found that IFIH1 (NM_022168.4), that encodes for Melanoma Differentiation-Associated Protein 5 (MDA5) is significantly up-regulated in the SARS-CoV-2 infected samples (Supplementary Table S7, P-adjusted = 7.46e-137). This is in line with findings indicating that the IFN response upon SARS-CoV-2 infection is primarily regulated by MDA5 (Yin et al, 2021). Since ADAR1 is known to prevent MDA5 from sensing dsRNA (Liddicoat et al, 2015), this result strengthening the conclusion that ADAR1 is largely involves in the immune response following SARS-CoV-2.…”

Section: Sars Cov-2 Infection Results In An Extensive A-to-i Hyper Rna Editing and Upregulation Of Adar1 Enzymesupporting

confidence: 88%

RESIC: A tool for comprehensive adenosine to inosine RNA Editing Site Identification and Classification

Light

Haas

Yazbak

et al. 2021

Preprint

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Adenosine to inosine (A-to-I) RNA editing, the most prevalent type of RNA editing in metazoans, is carried out by adenosine deaminases (ADARs) in double-stranded RNA regions. Several computational approaches have been recently developed to identify A-to-I RNA editing sites from sequencing data, each addressing a particular issue. Here we present RESIC, an efficient pipeline that combines several approaches for the detection and classification of RNA editing sites. The pipeline can be used for all organisms and can use any number of RNA-sequencing datasets as input. RESIC provides 1. The detection of editing sites in both repetitive and non-repetitive genomic regions; 2. The identification of hyper-edited regions; 3. Optional exclusion of polymorphism sites to increase reliability, based on DNA, and ADAR-mutant RNA sequencing datasets, or SNP databases. We demonstrate the utility of RESIC by applying it to human, successfully overlapping and extending the list of known putative editing sites. We further tested changes in the patterns of A-to-I RNA editing, and RNA abundance of ADAR enzymes, following SARS-CoV-2 infection in human cell lines. Our results suggest that upon SARS-CoV-2 infection, compared to mock, the number of hyper editing sites is increased, and in agreement, the activity of ADAR1, which catalyzes hyper-editing, is enhanced. These results imply the involvement of A-to-I RNA editing in conceiving the unpredicted phenotype of COVID-19 disease. RESIC code is open-source and is easily extendable.

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“…In this study, consistent with several recent reports 19–21 , we identified Calu-3 cells as a suitable model system for the study of innate immune responses to SARS-CoV-2 infection in vitro .These adenocarcinoma-derived lung epithelial cells expressed key proteins of RNA- and DNA-sensing pathways, responded to stimulation with type I IFN, and were highly infected by SARS-CoV-2. Importantly, SARS-CoV-2 induced transcription of the genes encoding type I and III IFNs, as well as pro-inflammatory cytokines in these cells.…”

Section: Discussionsupporting

confidence: 89%

“…In Calu-3 cells, RIG-I was largely dispensable for the antiviral cytokine response to infection. While our study was in preparation, other manuscripts reported MDA5 as the cellular sensor that recognises SARS-CoV-2 infection 19,20 . These reports included both siRNA-mediated knockdown and genetic ablation in Calu-3 cells.…”

Section: Discussionmentioning

confidence: 85%

“…However, it is important to note that some residual STING protein was still present in the targeted cells (Fig 3A), so it is possible that cytosolic DNA sensing by cGAS/STING induces the expression of TNF in response to SARS-CoV-2. Moreover, the study by Yin et al reported that, in addition to MDA5-MAVS, the receptors LGP2 and NOD1 are also required for the type I IFN response to SARS-CoV-2 in Calu-3 cells 19 . LGP2 is an RLR and may function to amplify MDA5-mediated responses 38 , whereas NOD1 was recently found to play a role in facilitating RLR activation 39 .…”

Section: Discussionmentioning

confidence: 99%

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The RNA sensor MDA5 detects SARS-CoV-2 infection

Sampaio

Chauveau

Hertzog

et al. 2021

Preprint

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Human cells respond to infection by SARS-CoV-2, the virus that causes COVID-19, by producing cytokines including type I and III interferons (IFNs) and proinflammatory factors such as IL6 and TNF. IFNs can limit SARS-CoV-2 replication but cytokine imbalance contributes to severe COVID-19. We studied how cells detect SARS-CoV-2 infection. We report that the cytosolic RNA sensor MDA5 was required for type I and III IFN induction in the lung cancer cell line Calu-3 upon SARS-CoV-2 infection. Type I and III IFN induction further required MAVS and IRF3. In contrast, induction of IL6 and TNF was independent of the MDA5-MAVS-IRF3 axis in this setting. We further found that SARS-CoV-2 infection inhibited the ability of cells to respond to IFNs. In sum, we identified MDA5 as a cellular sensor for SARS-CoV-2 infection that induced type I and III IFNs.

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MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells

Cited by 335 publications

References 65 publications

Differential roles of RIG-I-like receptors in SARS-CoV-2 infection

Differential roles of RIG-I-like receptors in SARS-CoV-2 infection

RESIC: A tool for comprehensive adenosine to inosine RNA Editing Site Identification and Classification

The RNA sensor MDA5 detects SARS-CoV-2 infection

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