Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs

Rebendenne, Antoine; Roy, Priyanka; Bonaventure, Boris; Valadão, Ana Luiza Chaves; Desmarets, Lowiese; Arnaud-Arnould, Mary; Rouillé, Yves; Tauziet, Marine; Giovannini, Donatella; Touhami, Jawida; Lee, Yenarae; DeWeirdt, Peter C; Hegde, Mudra; Urbach, Serge; Koulali, Khadija El; Gracia, Francisco Garcia de; McKellar, Joe; Dubuisson, Jean; Wencker, Mélanie; Belouzard, Sandrine; Moncorgé, Olivier; Doench, John G.; Goujon, Caroline

doi:10.1038/s41588-022-01110-2

Cited by 62 publications

(64 citation statements)

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“…We previously identified DYRK1A as a pro-viral gene for both SARS-CoVs and MERS-CoV in Vero-E6 cells and Calu-3 cells 22,23 . Additional recent independent screens in Vero-E6 and Calu-3 cells have confirmed our initial finding of DYRK1A as a host dependency factor for SARS-CoV-2 33,34 .…”

Section: Discussionsupporting

confidence: 79%

“…1A ). In another screen, DYRK1A was the third most strongly enriched hit after ACE2 33 . We generated single-cell knockout (KO) cells of DYRK1A in Vero-E6 cells using CRISPR/Cas9 to validate screening results and clarify the pro-viral mechanism underlying DYRK1A activity in coronavirus infection ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…During the COVID-19 pandemic, a number of genome-wide CRISPR/Cas9 screens have been performed to unveil host factors that regulate SARS-CoV-2 infection 22,23,[27][28][29][30][31][32][33]91,92 . We previously identified DYRK1A as a pro-viral gene for both SARS-CoVs and MERS-CoV in Vero-E6 cells and Calu-3 cells 22,23 .…”

Section: Discussionmentioning

confidence: 99%

“…Our group and others recently identified DYRK1A as a critical host factor for SARS-CoV-2, MERS-CoV, and chimeric HKU5 (bat coronavirus) expressing the SARS-CoV-1 spike (HKU5-SARS-CoV-1-S) in a genome-wide CRISPR/Cas9 inactivation screen in Vero-E6 cells 22,33 . In two additional independent genome-wide CRISPR screens in Calu-3 human immortalized lung cancer cells, DYRK1A was also identified as a top pro-viral gene for SARS-CoV-2 23,33 . By comparing the top 10,000 enriched genes ranked by z-score for SARS-CoV-2 across Vero-E6 and Calu-3 cells, we identified DYRK1A as second most strongly enriched gene after only ACE2 22,23 (Fig.…”

Section: Dyrk1a Promotes Viral Entry For Sars-covs and Mers-covmentioning

confidence: 99%

“…While reproducibility between screens was excellent when performed on the same cell type, there was otherwise limited overlap across hits in these loss of function screens [27][28][29][30][31][32] . One notable exception was DYRK1A, which was a top enriched hit in both Vero-E6 and Calu-3 cells 22,23,33,34 . Interestingly, DYRK1A was not a hit in cell lines exogenously overexpressing ACE2, such as A549, Huh7.5, or HeLa cells [27][28][29][30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

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Kinase-independent activity of DYRK1A promotes viral entry of highly pathogenic human coronaviruses

Strine

Cai

Jin

et al. 2022

Preprint

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Identifying host genes essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to reveal novel drug targets and further our understanding of coronavirus disease 2019 (COVID-19). We previously performed a genome-wide CRISPR/Cas9 screen to identify pro-viral host factors for highly pathogenic human coronaviruses. Very few host factors were required by diverse coronaviruses across multiple cell types, but DYRK1A was one such exception. Although its role in coronavirus infection was completely unknown, DYRK1A encodes Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A and regulates cell proliferation, and neuronal development, among other cellular processes. Interestingly, individuals with Down syndrome overexpress DYRK1A 1.5-fold and exhibit 5-10x higher hospitalization and mortality rates from COVID-19 infection. Here, we demonstrate that DYRK1A regulates ACE2 and DPP4 transcription independent of its catalytic kinase function to support SARS-CoV, SARS-CoV-2, and MERS-CoV entry. We show that DYRK1A promotes DNA accessibility at the ACE2 promoter and a putative distal enhancer, facilitating transcription and gene expression. Finally, we validate that the pro-viral activity of DYRK1A is conserved across species using cells of monkey and human origin and an in vivo mouse model. In summary, we report that DYRK1A is a novel regulator of ACE2 and DPP4 expression that may dictate susceptibility to multiple highly pathogenic human coronaviruses. Whether DYRK1A overexpression contributes to heightened COVID-19 severity in individuals with Down syndrome through ACE2 regulation warrants further future investigation.

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Section: Discussionsupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Dyrk1a Promotes Viral Entry For Sars-covs and Mers-covmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Kinase-independent activity of DYRK1A promotes viral entry of highly pathogenic human coronaviruses

Strine

Cai

Jin

et al. 2022

Preprint

Self Cite

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Scramblases and virus infection

et al. 2022

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The asymmetric distribution of lipids, maintained by flippases/floppases and scramblases, plays a pivotal role in various physiologic processes. Scramblases are proteins that move phospholipids between the leaflets of the lipid bilayer of the cellular membrane in an energy-independent manner. Recent studies have indicated that viral infection is closely related to cellular lipid distribution. The level and distribution of phosphatidylserine (PtdSer) in cells have been demonstrated to be critical regulators of viral infections. Previous studies have supported that the infection of human immunodeficiency virus (HIV), Zika virus, Ebola virus (EBOV), influenza virus, and dengue fever virus require the externalization of phospholipids mediated by scramblases, which are also involved in the pathogenicity of the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we review the relationship of scramblases with viruses and the potential viral effector proteins that might utilize host scramblases.

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Deep phenotyping of the lipidomic response in COVID‐19 and non‐COVID‐19 sepsis

Meng,

Sengupta,

Ricciotti

et al. 2023

Clinical & Translational Med

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BackgroundLipids may influence cellular penetrance by viral pathogens and the immune response that they evoke. We deeply phenotyped the lipidomic response to SARs‐CoV‐2 and compared that with infection with other pathogens in patients admitted with acute respiratory distress syndrome to an intensive care unit (ICU).MethodsMass spectrometry was used to characterise lipids and relate them to proteins, peripheral cell immunotypes and disease severity.ResultsCirculating phospholipases (sPLA2, cPLA2 (PLA2G4A) and PLA2G2D) were elevated on admission in all ICU groups. Cyclooxygenase, lipoxygenase and epoxygenase products of arachidonic acid (AA) were elevated in all ICU groups compared with controls. sPLA2 predicted severity in COVID‐19 and correlated with TxA2, LTE4 and the isoprostane, iPF2α‐III, while PLA2G2D correlated with LTE4. The elevation in PGD2, like PGI2 and 12‐HETE, exhibited relative specificity for COVID‐19 and correlated with sPLA2 and the interleukin‐13 receptor to drive lymphopenia, a marker of disease severity. Pro‐inflammatory eicosanoids remained correlated with severity in COVID‐19 28 days after admission. Amongst non‐COVID ICU patients, elevations in 5‐ and 15‐HETE and 9‐ and 13‐HODE reflected viral rather than bacterial disease. Linoleic acid (LA) binds directly to SARS‐CoV‐2 and both LA and its di‐HOME products reflected disease severity in COVID‐19. In healthy marines, these lipids rose with seroconversion. Eicosanoids linked variably to the peripheral cellular immune response. PGE2, TxA2 and LTE4 correlated with T cell activation, as did PGD2 with non‐B non‐T cell activation. In COVID‐19, LPS stimulated peripheral blood mononuclear cell PGF2α correlated with memory T cells, dendritic and NK cells while LA and DiHOMEs correlated with exhausted T cells. Three high abundance lipids – ChoE 18:3, LPC‐O‐16:0 and PC‐O‐30:0 – were altered specifically in COVID. LPC‐O‐16:0 was strongly correlated with T helper follicular cell activation and all three negatively correlated with multi‐omic inflammatory pathways and disease severity.ConclusionsA broad based lipidomic storm is a predictor of poor prognosis in ARDS. Alterations in sPLA2, PGD2 and 12‐HETE and the high abundance lipids, ChoE 18:3, LPC‐O‐16:0 and PC‐O‐30:0 exhibit relative specificity for COVID‐19 amongst such patients and correlate with the inflammatory response to link to disease severity.

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Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs

Cited by 62 publications

References 64 publications

Kinase-independent activity of DYRK1A promotes viral entry of highly pathogenic human coronaviruses

Kinase-independent activity of DYRK1A promotes viral entry of highly pathogenic human coronaviruses

Scramblases and virus infection

Deep phenotyping of the lipidomic response in COVID‐19 and non‐COVID‐19 sepsis

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