Dysregulation of type I interferon responses in COVID-19

Acharya, Dhiraj; Liu, Guanqun; Gack, Michaela U.

doi:10.1038/s41577-020-0346-x

Cited by 396 publications

(442 citation statements)

References 11 publications

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“…Suppression of IFN signaling by SARS-CoV-2 has been reported by several studies 26,27 , possibly explaining only a moderate effect of SARS-CoV-2 infection on dACE2 induction in our experiments. While type I and type III IFNs are barely detectable in COVID-19 patients 28,29 , high levels of IFN-γ have been reported 29,30 . Specifically, a 3'-scRNA-seq analysis showed ACE2 induction by SARS-CoV-2 infection in ciliated epithelia, where high levels of IFN-γ producing immune cells were also detected 5 .…”

Section: Discussionmentioning

confidence: 94%

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Onabajo

Banday

Yan

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, primate-specific isoform of ACE2, which we designate as deltaACE2 (dACE2). We demonstrate that dACE2, but not ACE2, is an ISG. In vitro, dACE2, which lacks 356 N-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results reconcile current knowledge on ACE2 expression and suggest that the ISG-type induction of dACE2 in IFN-high conditions created by treatments, inflammatory tumor microenvironment, or viral co-infections is unlikely to affect the cellular entry of SARS-CoV-2 and promote infection.

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Section: Discussionmentioning

confidence: 94%

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Onabajo

Banday

Yan

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…In particular, tocilizumab, an anti-IL-6 receptor monoclonal antibody, has been tested in COVID-19 patients and showed promising results [13]. Conversely, IFN-beta expression is inhibited by SARS-CoV-1 infections [14], while a general type I interferon inhibition has been observed in SARS-CoV-2 infections [15]. Type I interferons have antiviral properties and may be actively repressed by SARS-CoV-1 and SARS-CoV-2 during infection to escape the host immune response.…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of MERS, SARS and COVID-19 in vitro Infection Datasets Reveals Common Patterns in Gene and Protein Expression

Martinelli¹,

Akhmedov²,

Kwee³

2020

Preprint

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Three lethal lower respiratory tract coronavirus epidemics have occurred over the past 20 years. This coincided with major developments in genome-wide gene and protein expression analysis, resulting in a wealth of datasets in the public domain. Seven such in vitro studies were selected for comparative bioinformatic analysis through the VirOmics Playground, a user-friendly visualisation and exploration platform we recently developed. Despite the heterogeneous nature of the data sets, several commonalities could be observed across studies and species. Differences, on the other hand, reflected not only variations between species, but also other experimental variables, such as cell lines used for the experiments, infection protocols and potential discrepancies between transcriptome and proteome data. The results presented here are available online and can be replicated through the VirOmics Playground.

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“…Previously, we and several others have proposed structural simulation models of ACE2 and the viral S-Receptor binding domain (S-RBD) to predict SARS-CoV2 susceptibility across representative vertebrates, especially major domestic and wild mammalian species [30][31][32][33]. The structural affinity between ACE2 and S-RBD plays a primary role in the viral attachment and accessibility in cells, and the specific early cellular responses that regulate ACE2 expression and signal early immune responses determine the host susceptibility to the virus [34][35][36][37][38][39][40]. We propose an integrative model, which incorporates both ACE2-RBD structural affinity (primarily determined by cross-species genetic difference) and epigenetic regulation of key genes during the early phase of the virus-host interaction, to predict host COVID-19 susceptibility and disease progression [30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

“…Ang2-AT1R activation also induces pyroptosis, a highly inflammatory form of programmed cell death accompanying cytotoxicity caused by viral infections [41,45,46]. Aggregately, SARS-CoV2 itself also activates NF-κB via various pattern recognition receptors (PPRs) [33][34][35][36][37][38][39][40]. Therefore, IL-6 and IL-6 AMP are biomarkers of hyperactivation of inflammatory machinery exacerbated by ACE2 blocking and viral infection, which represent key cytokines in deciphering cytokine-related syndrome and disease progression of COVID-19 [41,45,46].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Evolution of ACE2 and IL-6 Genes as Non-Canonical Interferon-Stimulated Genes Correlate to COVID-19 Susceptibility in Vertebrates

Sang

Tian

Miller

et al. 2020

Preprint

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Current novel coronavirus disease (COVID-19) has spread globally within a matter of months. The virus establishes a success in balancing its deadliness and contagiousness, and causes substantial differences in susceptibility and disease progression in people of different ages, genders and pre-existing comorbidities. Since these host factors are subjected to epigenetic regulation, relevant analyses on some key genes underlying COVID-19 pathogenesis were performed to longitudinally decipher their epigenetic correlation to COVID-19 susceptibility. The genes of host angiotensin-converting enzyme 2 (ACE2, as the major virus receptor) and interleukin (IL)-6 (a key immune-pathological factor triggering cytokine storm) were shown to evince active epigenetic evolution via histone modification and cis/trans-factors interaction across different vertebrate species. Extensive analyses revealed that ACE2 ad IL-6 genes are among a subset of non-canonical interferon-stimulated genes (non-ISGs), which have been designated recently for their unconventional responses to interferons (IFNs) and inflammatory stimuli through an epigenetic cascade. Furthermore, significantly higher positive histone modification markers and position weight matrix (PWM) scores of key cis-elements corresponding to inflammatory and IFN signaling, were discovered in both ACE2 and IL6 gene promoters across representative COVID-19-susceptible species compared to unsusceptible ones. Findings characterize ACE2 and IL-6 genes as non-ISGs that respond differently to inflammatory and IFN signaling from the canonical ISGs and their epigenetic properties may serve as biomarkers to longitudinally predict COVID-19 susceptibility in vertebrates and partially explain COVID-19 inequality in people of different subgroups.

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Dysregulation of type I interferon responses in COVID-19

Abstract: Infection with SARS-CoV-2 can lead to excessive production of pro-inflammatory cytokines, but the production of type I interferons, which are key antiviral mediators, is reportedly blunted. Here, we discuss how imbalanced interferon responses may contribute to the pathology of COVID-19.

Cited by 396 publications

References 11 publications

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Meta-analysis of MERS, SARS and COVID-19 in vitro Infection Datasets Reveals Common Patterns in Gene and Protein Expression

Epigenetic Evolution of ACE2 and IL-6 Genes as Non-Canonical Interferon-Stimulated Genes Correlate to COVID-19 Susceptibility in Vertebrates

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