Type I IFN immunoprofiling in COVID-19 patients

Trouillet‐Assant, Sophie; Viel, Sébastien; Gaymard, Alexandre; Pons, Sylvie; Richard, Jean-Christophe; Perret, Magali; Villard, Marine; Brengel‐Pesce, Karen; Lina, Bruno; Mezidi, Mehdi; Bitker, Laurent; Belot, Alexandre; Mouton, William; Oriol, Guy; Compagnon, Christelle; Generenaz, Laurence; Cheynet, Valérie; Ader, Florence; Becker, Agathe; Benech, Nicholas; Chauvelot, Pierre; Chidiac, Christian; Conrad, Anne; Ferry, Tristan; Miailhes, Patrick; Perpoint, Thomas; Perry, Marielle; Pouderoux, Cécile; Roux, Sandrine; Triffault-Fillit, Claire; Valour, Florent; Yonis, Hodane; Chauvelot, Louis; Chabert, Paul; Provoost, Judith; David, Guillaume; Folliet, Laure; Lecam, Pierre; Billaud, Geneviève; Bouscambert, Maude; Escuret, Vanessa; Frobert, Émilie; Bal, Antonin; Destras, Grégory; Josset, Laurence; Morfin, Florence; Munier, Clément; Valette, Martine; Venet, Fabienne; Garnier, L.; Pescarmona, Rémi; Lombard, Christine; Walzer, Thierry

doi:10.1016/j.jaci.2020.04.029

Cited by 249 publications

(265 citation statements)

References 6 publications

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“…Although there is conflicting data on the presence of an IFN gene signature (IGS) and whether SARS-CoV2 infection induces a robust IFN response (Blanco-Melo et al, 2020;Trouillet-Assant et al, 2020;Wei et al, 2020), we observed increased expression of Type I IFN genes (IFNA4, IFNA6, IFNA10) and significant enrichment of the common Type I and Type II IGS, including enrichment of IFNA2, IFNB1 and IFNG gene signatures specifically in the lung tissue ( Figure 2A&B). Furthermore, we detected increased expression of genes found to be important for the anti-viral innate immune response (IFIH1, DDX58, EIF2AK2, OAS2) and decreased expression of negative regulators of this response (IRF2BP1, SKIV2L) in both the lung and airway compartments ( Figure 2C) (Fischer et al, 2020).…”

Section: Covid-19 Patientsmentioning

confidence: 65%

Comprehensive Transcriptomic Analysis of COVID-19 Blood, Lung, and Airway

Daamen

Bachali

Owen

et al. 2020

Preprint

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SARS-CoV2 is a previously uncharacterized coronavirus and causative agent of the COVID-19 pandemic. The host response to SARS-CoV2 has not yet been fully delineated, hampering a precise approach to therapy. To address this, we carried out a comprehensive analysis of gene expression data from the blood, lung, and airway of COVID-19 patients. Our results indicate that COVID-19 pathogenesis is driven by populations of myeloid-lineage cells with highly inflammatory but distinct transcriptional signatures in each compartment. The relative absence of cytotoxic cells in the lung suggests a model in which delayed clearance of the virus may permit exaggerated myeloid cell activation that contributes to disease pathogenesis by the production of inflammatory mediators. The gene expression profiles also identify potential therapeutic targets that could be modified with available drugs. The data suggest that transcriptomic profiling can provide an understanding of the pathogenesis of COVID-19 in individual patients.3 1 Methods Read quality, trimming, mapping and summarizationPublicly available data sets used in this study are listed in Table S1. RNA-seq data were processed using a consistent workflow using FASTQC, Trimmomatic, STAR, Sambamba, and featureCounts. As described below SRA files were downloaded and converted into FASTQ format using SRA toolkit. Read ends and adapters were trimmed with Trimmomatic (v0.38) using a sliding window, ilmnclip, and headcrop filters. Both datasets were head cropped at 6bp and adapters were removed before read alignment.Reads were mapped to the human reference genome hg38 using STAR, and the .sam files were converted to sorted .bam files using Sambamba. Read counts were summarized using the featureCounts function of the Subread package (v1.61.)The RNA-seq tools are all free, open source programs available at the following web addresses SRA toolkit -https

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Section: Covid-19 Patientsmentioning

confidence: 65%

Comprehensive Transcriptomic Analysis of COVID-19 Blood, Lung, and Airway

Daamen

Bachali

Owen

et al. 2020

Preprint

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“…Wei and colleagues demonstrated that genesfunctioning in viral defense, such as ISGs, are highly expressed inperipheral blood mononuclear cells of SARS-CoV-2 infectedindividuals requiring intensive care [16]. In one study, peak IFNα2levels occurred on days 8-10 of symptom onset and graduallydecreased over the following 2-3 weeks in critically ill adults [17].…”

Section: Resultsmentioning

confidence: 99%

Fatal Central Nervous System Co-Infection with SARS-CoV-2 and Tuberculosis in a Healthy Child

Freij

Gebara

Tariq

et al. 2020

Preprint

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Background. Central and peripheral nervous system symptoms and complications are being increasingly recognized among individuals with pandemic SARS-CoV-2 infections, but actual detection of the virus or its RNA in the central nervous system has rarely been sought or demonstrated. Severe or fatal illnesses are attributed to SARS-CoV-2, generally without attempting to evaluate for alternative causes or co-pathogens.Case presentation. A five-year-old girl with fever and headache was diagnosed with acute SARS-CoV-2-associated meningoencephalitis based on the detection of its RNA on a nasopharyngeal swab, cerebrospinal fluid analysis, and magnetic resonance imaging findings. Serial serologic tests for SARS-CoV-2 IgG and IgA showed seroconversion, consistent with an acute infection. Mental status and brain imaging findings gradually worsened despite antiviral therapy and intravenous dexamethasone. Decompressive suboccipital craniectomy for brain herniation with cerebellar biopsy on day 30 of illness, shortly before death, revealed SARS-CoV-2 RNA in cerebellar tissue using the Centers for Disease Control and Prevention 2019-nCoV Real-Time Reverse Transcriptase-PCR Diagnostic Panel. On histopathology, necrotizing granulomas with numerous acid-fast bacilli were visualized, and Mycobacterium tuberculosis complex DNA was detected by PCR. Ventricular cerebrospinal fluid that day was negative for mycobacterial DNA. She had no known exposures to tuberculosis and no chest radiographic findings to suggest it. All 6 family members had normal chest radiographs and negative interferon-γ release assay results. The source of her tuberculous infection was not identified, and further investigations by the local health department were not possible because of the State of Michigan-mandated lockdown for control of SARS-CoV-2 spread.Conclusion. The detection of SARS-CoV-2 RNA in cerebellar tissue and the demonstration of seroconversion in IgG and IgA assays was consistent with acute SARS-CoV-2 infection of the central nervous infection. However, the cause of death was brain herniation from her rapidly progressive central nervous system tuberculosis. SARS-CoV-2 may mask or worsen occult tuberculous infection with severe or fatal consequences.

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“…Here we show that in-vitro, SARS-CoV2 PLpro was able to cleave IRF3 and validated that the effect could be observed in relevant virus infected cells ( Figure 5). Direct proteolytic cleavage of IRF3 may contribute to the reduction of type I interferon production observed in COVID19 patients [31,32]. TAB1 is part of the TAB1/2/3/TAK1 complex [70] that regulates the activity of TAK1 (TGFβ-activated kinase 1), in response to different stimuli including TGFβ, IL1, TNFα and upon viral and bacterial infection [71,72].…”

Section: Irf3 Tab1 and Nlrp12 Are Important Components That Drive Thmentioning

confidence: 99%

“…Structure-function correlative analysis followed by comparative alignment of IRF3 and NLRP12 homologs across relevant mammalian orders reveal the potential explanatory power of our findings. The cleavage of IRF3 could explain the enigmatically blunted type-I IFN response that have been noted in early studies of SARS-CoV-2 infections [31,32], while the NSP5 mediated cleavage of NLRP12 might explain the hyperinflammatory response linked to severe COVID-19 disease [33,34]. Indeed, the lack or presence of cognate cleavage motifs in IRF3 and NLRP12 homologs presents interesting correlations with the presentation of disease in animal models; our results will enable the development of more effective animal models for severe COVID-19.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

Moustaqil

Ollivier

Chiu

et al. 2020

Preprint

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The genome of SARS-CoV-2 (SARS2) encodes for two viral proteases (NSP3/ papain-like protease and NSP5/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 and NSP5 of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 NSP3 and NSP5 target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 and NSP5 on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 or NSP5, we could readily detect cleavage of cognate HIIPs on SDS-page gels. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients. Surprisingly, both NLRP12 and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for in-depth studies into the pathophysiology of COVID-19 and should facilitate the search or development of more effective animal models for severe COVID-19. Finally, we discovered that one particular species of bats, David's Myotis, possesses the five cleavage sites found in humans for NLRP12, TAB1 and IRF3. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.

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Type I IFN immunoprofiling in COVID-19 patients

Abstract: B enite, d the National Referee Centre for Rheumatic and AutoImmune and Systemic diseases in childrEn (RAISE), and

Cited by 249 publications

References 6 publications

Comprehensive Transcriptomic Analysis of COVID-19 Blood, Lung, and Airway

Comprehensive Transcriptomic Analysis of COVID-19 Blood, Lung, and Airway

Fatal Central Nervous System Co-Infection with SARS-CoV-2 and Tuberculosis in a Healthy Child

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

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