Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis

ABSTRACT: We and others have previously shown that the SARS-CoV-2 accessory protein ORF6 is a powerful antagonist of the interferon signaling pathway by directly interacting with the Nup98-Rae1 complex at the nuclear pore, and disrupting bi-directional nuclear-cytoplasmic trafficking. In this study, we further assessed the role of ORF6 during infection using recombinant SARS-CoV-2 viruses carrying either a deletion or a well characterized M58R loss-of-function mutation in ORF6. We unambiguously show that ORF6 plays a key non-redundant role in the antagonism of IFN signaling by interfering with karyopherin-mediated nuclear import during SARS-CoV-2 infection both in vitro, and in the Syrian hamster model in vivo. In addition, we found that by contributing to the inhibition of cellular mRNA export, ORF6 expression significantly remodels the host cell proteome upon infection. Importantly, we also unravel a previously unrecognized function of ORF6 in the modulation of viral protein expression, which is independent of its function at the nuclear pore. Lastly, we characterized the ORF6 D61L mutation that recently emerged in Omicron BA.2 and BA.4 subvariants and demonstrated that it is able to disrupt ORF6 protein functions at the NPC and to impair SARS-CoV-2 innate immune evasion strategies. Altogether, our findings not only further highlight the key role of ORF6 in the antagonism of the antiviral innate immune response, but also emphasize the importance of studying the role of non-spike mutations to better understand the mechanisms governing differential pathogenicity and immune evasion strategies of SARS-CoV-2.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215433 | GEO | 2023/08/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that is a serious global health threat. Evasion of interferon-mediated antiviral signaling is a common defense strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to efficiently block STAT1 and STAT2 nuclear translocation in order to impair transcriptional induction of interferon (IFN) stimulated genes (ISGs). Our results demonstrate that the viral accessory protein Orf6 exerts this anti-IFN activity. We found that SARS-CoV-2 Orf6 localizes at the nuclear pore complex (NPC) where it directly interacts with Nup98-Rae1 via its C-terminal domain to impair docking of cargo-receptor complexes and disrupt nuclear import functions. In addition, we show that a methionine-to-arginine substitution at residue 58 impairs Orf6 binding to the Nup98-Rae1 complex and abolishes its IFN antagonistic function. All together our data unravel a new mechanism of viral antagonism in which a virus hijacks the Nup98-Rae1 complex to overcome the antiviral action of IFN.

2020-10-20 | GSE159593 | GEO

Transcriptomic Analysis of THP-1 Cells Electroporated with GFP-EV or GFP-SARS-CoV-2-ORF6

Project description:SARS-CoV-2 ORF6 plays a pivotal role as an accessory protein in modulating the innate immune signaling pathway during SARS-CoV-2 infection. Our study presents a comprehensive analysis of transcriptomes within innate immune cells overexpressing SARS-CoV-2-ORF6. This transcriptomic analysis facilitates rapid exploration of biological networks regulated by ORF6 and allows for a detailed examination of its multifaceted roles across diverse innate immune signaling pathways.

2024-02-18 | GSE249500 | GEO

Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism [ATAC-seq]

Project description:Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential therapeutics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-induced antiviral activity and its susceptibility to viral antagonism remain incompletely understood. iBET treatment transiently inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. Our functional assays confirmed JQ-1-mediated downregulation of angiotensin-converting enzyme 2 (ACE2) expression and multi-omics analysis uncovered induction of an antiviral NRF-2-mediated cytoprotective response as an additional antiviral component of JQ-1 treatment. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variants. JQ-1 antiviral activity was transient in human bronchial airway epithelial cells (hBAECs) treated prior to infection and absent when administered therapeutically. We propose that JQ-1 exerts pleiotropic effects that collectively induce a transient antiviral state that is ultimately nullified by an established SARS-CoV-2 infection, raising questions about the clinical suitability of iBETs in the context of COVID-19.

2023-09-18 | GSE239587 | GEO

Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism [RNA-Seq]

2023-09-18 | GSE239585 | GEO

SARS-CoV-2 spike sequence dictates host TP53 activity and COVID-19 pathogenicity

Project description:SARS-CoV-2 induces widespread transcriptomic changes in host cells upon infection, in part through activation and modulation of innate immunity pathways and downstream gene regulation. However, the mechanisms by which SARS-CoV-2 and its evolutionary variants differentially affect host cell transcriptomic states remain largely unclear. Through chromatin proteomic (iDAPT-MS) analysis, we found that although SARS-CoV-2 and other pathogenic coronaviruses exhibit similar proteomic shifts on chromatin, SARS-CoV-2 uniquely promotes TP53 nuclear accumulation and activation. Parallel assessment of SARS-CoV-2 viral protein expression on host chromatin states (ATAC-seq) identifies intracellular spike protein as a key determinant of virus-mediated chromatin accessibility changes. Multilevel chromatin profiling reveals increased TP53 nuclear accumulation, TP53-associated chromatin accessibility changes, and TP53 target gene activation upon expression of SARS-CoV-2 alpha (B.1.1.7) and delta (B.1.617.2) spike variants relative to the ancestral spike sequence. TP53, ACE2, and furin cleavage are required for these changes, driving decreased cellular proliferation, increased cellular senescence, and increased cytokine release. Finally, BA.1 but not BA.2, BA.2.12.1, nor BA.4/BA.5 spike expression leads to attenuated TP53 activity and fusogenicity relative to ancestral spike. Our findings implicate spike-mediated host TP53 activation as a “rheostat” of COVID-19 pathogenicity.

2023-09-09 | PXD034648 | Pride

Limited cross-variant immune response from SARS-CoV-2 Omicron BA.2 in naïve but not previously infected outpatients

Project description:Omicron is currently the dominant SARS-CoV-2 variant and several sublineages have emerged. Questions remain about the impact of previous SARS-CoV-2 exposure on cross-variant immune responses elicited by the SARS-CoV-2 Omicron sublineage BA.2 compared to BA.1. Here we show that without previous history of COVID-19, BA.2 infection induces a reduced immune response against all variants of concern (VOC) compared to BA.1 infection. The absence of ACE2 binding in sera of previously naïve BA.1 and BA.2 patients indicates a lack of meaningful neutralization. In contrast, anti-spike antibody levels and neutralizing activity greatly increased in the BA.1 and BA.2 patients with a previous history of COVID-19. Transcriptome analyses of peripheral immune cells showed significant differences in immune response and specific antibody generation between BA.1 and BA.2 patients as well as significant differences in the expression of specific immune genes. In summary, prior infection status significantly impacts the innate and adaptive immune response against VOC following BA.2 infection.

2022-12-20 | GSE205244 | GEO

Total Proteomics of SARS-CoV-2 variants

Project description:The ancestral SARS-CoV-2 strain that initiated the Covid-19 pandemic at the end of 2019 has rapidly mutated into multiple variants of concern with variable pathogenicity and increasing immune escape strategies. However, differences in host cellular antiviral responses upon infection with SARS-CoV-2 variants remains elusive. Leveraging whole cell proteomics, we determined host signalling pathways that are differentially modulated upon infection with the clinical isolates of the ancestral SARS-CoV-2 B.1 and the variants of concern Delta and Omicron BA.1. Our findings illustrate alterations in the global host proteome landscape upon infection with SARS-CoV-2 variants and the resulting host immune responses. Additionally, viral proteome kinetics reveal declining levels of viral protein expression during Omicron BA.1 infection when compared to ancestral B.1 and Delta variants, consistent with its reduced replication rates. Moreover, molecular assays reveal deferral activation of specific host antiviral signalling upon Omicron BA.1 and BA.2 infection. Our study provides an overview of host proteome profile of multiple SARS-CoV-2 variants and brings forth a better understanding of the instigation of key immune signalling pathways causative for the differential pathogenicity of SARS-CoV-2 variants.

2023-05-10 | PXD037265 | Pride

A Single Intranasal Vaccination with a Rationally Attenuated SARS-CoV-2 Elicits Strong Humoral Immune Response and Is Protective in Syrian Hamsters

Project description:Very few live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are currently in pre-clinical or clinical development. We rationally attenuated SARS-CoV-2 (isolate WA1/2020) by removing the polybasic cleavage site within the spike protein and the open reading frames (ORFs) 6-8, and by introducing a pair of mutations into the non-structural protein 1 (Nsp1). The derived virus (WA1-DPRRA-ORF6-8-Nsp1K164A/H165A) became severely attenuated in both the K18-human ACE2 (hACE2) transgenic mice and in Syrian hamsters. Transcriptomic profiling of nasal turbinates and lung tissues of infected Syrian hamsters confirmed that WA1-DPRRA-ORF6-8-Nsp1K164A/H165A attenuated the upregulation of proinflammatory pathways. A single intranasal immunization of just 100 PFU of the WA1-DPRRA-ORF6-8-Nsp1K164A/H165A elicited binding and neutralizing antibody responses in Syrian hamsters and completely protected against SARS-CoV-2-induced weight loss and pneumonia. These data demonstrate the feasibility of rational attenuation of SARS-CoV-2. WA1-DPRRA-ORF6-8-Nsp1K164A/H165A represents a promising live attenuated vaccine candidate.

2022-04-04 | GSE199922 | GEO

A Retrospective Cohort Study for Main Postoperative Complications After SARS-CoV-2 Infection

Project description:To explore the relationship between SARS-CoV-2 infection in different time before operation and postoperative main complications (mortality, main pulmonary and cardiovascular complications) 30 days after operation; To determine the best timing of surgery after SARS-CoV-2 infection.

| 12454 | ecrin-mdr-crc

Main Postoperative Complications After COVID-19

| 5792 | ecrin-mdr-crc