Epigenetic activation of antiviral sensors and effectors of interferon response pathways during SARS-CoV-2 infection
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ABSTRACT:
PROVIDER: PRJNA835413 | ENA |
REPOSITORIES: ENA
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Project description:We combined methylomics and transcriptomics data from four geographically distant and ethnically heterogeneous cohorts of COVID-19 patients, with the aim to assess causal interaction of SARS-CoV-2 virus with host methylome.
2022-07-20 | GSE202296 | GEO
Project description:Recent studies have shown that methylation changes identified in blood cells of COVID-19 patients have a potential to be used as biomarkers of SARS-CoV-2 infection outcomes. However, different studies have reported different subsets of epigenetic lesions that stratify patients according to the severity of infection symptoms, and more importantly, the significance of those epigenetic changes in the pathology of the infection is still not clear. We used methylomics and transcriptomics data from the largest so far cohort of COVID-19 patients from four geographically distant populations, to identify casual interactions of blood cells' methylome in pathology of the COVID-19 disease. We identified a subset of methylation changes that is uniformly present in all COVID-19 patients regardless of symptoms. Those changes are not present in patients suffering from upper respiratory tract infections with symptoms similar to COVID-19. Most importantly, the identified epigenetic changes affect the expression of genes involved in interferon response pathways and the expression of those genes differs between patients admitted to intensive care units and only hospitalized. In conclusion, the DNA methylation changes involved in pathophysiology of SARS-CoV-2 infection, which are specific to COVID-19 patients, can not only be utilized as biomarkers in the disease management but also present a potential treatment target.
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Project description:Type 1 interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control and immune-mediated pathology and have been successfully employed for the treatment of viral diseases. In humans, there are twelve IFN-alpha (α) subtypes, which activate downstream signalling cascades and result in a distinct pattern of immune responses and differential antiviral responses. In this project, we analysed the antiviral activity of IFNα subtypes towards SARS-CoV-2 to identify the underlying immune signatures and explore their therapeutic potential. Pre-treatment of primary human airway epithelial cells (hAEC) cells with different human IFN-α subtypes demonstrated distinct antiviral activities against SARS-CoV-2. We identified IFNα5 as one of the strongest antiviral acting IFNs against SARS-CoV-2 infection in this study. Dose-dependency studies displayed an additive effect when co-administered with the broad antiviral drug remdesivir in cell culture. Bulk transcriptomics of pre-treated hAEC revealed differentially expressed gene signatures, with IFNα subtype-specific distinct, intersecting and common genes. Proteomic analysis confirmed the expression of distinct interferon effectors for the subset of highly antiviral IFNα5. Therefore, our data elucidate molecular antiviral host responses upon treatment with type I IFNs on several levels, knowledge which could aid in the development of novel therapeutic approaches.
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2023-11-24 | MSV000093478 | MassIVE
Project description:Two highly pathogenic human coronaviruses that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) have evolved proteins that can inhibit host antiviral responses, likely contributing to disease progression and high case-fatality rates. SARS-CoV-2 emerged in December 2019 to cause a global pandemic. Recent studies have shown that SARS-CoV-2 is unable to induce a robust type I interferon (IFN) response in human cells, leading to speculations about the ability of SARS-CoV-2 to inhibit innate antiviral responses. However, innate antiviral responses are dynamic in nature and gene expression levels rapidly change within minutes to hours. In this study, we have performed a time series RNA-seq analysis to identify early virus-host processes. SARS-CoV-2 infection upregulated transcripts for type I IFNs and interferon stimulated genes (ISGs) after 12 hours. Furthermore, we analyzed the ability of SARS-CoV-2 to inhibit type I IFN production and downstream antiviral signaling in human cells. Using exogenous stimuli, we discovered that SARS-CoV-2 is unable to modulate IFNb production and downstream expression of ISGs, such as IRF7 and IFIT1. Thus, data from our study indicate that SARS-CoV-2 may have evolved additional mechanisms, such as masking its nucleic acid from cellular immune response sensors to mount a dampened innate antiviral response. Further studies are required to fully identify the range of immune-modulatory strategies of SARS-CoV-2.
2021-05-20 | GSE151513 | GEO
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated Interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN- production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Senescent Huh7 cells in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection and SARS-CoV-2 effectively inhibited IFIT1 in these cells. Proteomic comparison between SARS-CoV-2, SARS-CoV and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Characterization of the role of different interferon stimulated genes on the inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.
2021-05-18 | PXD023450 | Pride
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2015-09-01 | E-GEOD-61413 | biostudies-arrayexpress
Project description:SARS-CoV-2 infection activates interferon-controlled signaling pathways and elicits a wide spectrum of immune responses and clinical manifestations in human patients. Here, we investigate the impact of prior vaccination on the innate immune response of hospitalized COVID-19 patients infected with the SARS-CoV-2 Beta variant through RNA sequencing of peripheral blood immune cells. Four patients had received the first dose of BNT162b2 about 11 days prior to the onset of COVID-19 symptoms and five patients were unvaccinated. Patients had received dexamethasone treatment. Immune transcriptomes were obtained at days 7-13, 20-32 and 42-60 after first symptomology. RNA-seq reveals an enhanced JAK-STAT-mediated immune transcriptome response at day 10 in vaccinated patients as compared to unvaccinated ones. This increase subsides by day 35. Expression of the gene encoding the antiviral protein oligoadenylate synthetase (OAS) 1, which is inversely correlated with disease severity, and other key antiviral proteins increases in the vaccinated group. We also investigate the immune transcriptome in naïve individuals receiving their first dose of BNT162b2 and identify a gene signature shared with the vaccinated COVID-19 patients. Our study demonstrates that RNA-seq can be used to monitor molecular immune responses elicited by the BNT162b2 vaccine, both in naïve individuals and in COVID-19 patients, and it provides a biomarker-based approach to systems vaccinology.
2022-06-21 | GSE174621 | GEO
Project description:Clinical data show SARS-CoV-2 infection causes activation of host inflammatory antiviral response, including the type I interferon pathway and the expression of many inflammatory cytokines, as well as the infiltration of neutrophils and macrophages. It has been hypothesized that the overt host inflammatory response is at least partially responsible for COVID-19 associated diffuse alveolar damage (DAD). Our research focuses on one defining feature of DAD, hyaline membrane formation which is characterized by fibrin deposition in lung airspace. With primary normal human bronchial/tracheal epithelial (NHBE) cells and human small airway epithelial cells (HSAEC) as in vitro models, we have evidence of turbidity assay, confocal microscopy, and scanning electron microscopy (SEM) proving that infection with field isolates of SARS-CoV-2 variants and SARS-CoV-2 spike pseudotyped lentiviruses (pSARS2) induces fibrin clot formation in the NHBE and HSAEC cells. We have also observed that the infection-induced fibrin formation in NHBE and HSAEC cells requires thrombin but is independent of tissue factor and other classical plasma coagulation factors. In addition, we have validated involvement of type II transmembrane serine proteases (TMPRSS) in the activation of thrombin, the last enzyme in the coagulation cascade. Therefore, we performed RNA sequencing analyses to infected NHBE and HSAEC cells and further investigated how SARS-CoV-2 variants and pSARS2 regulate type I interferon response, antiviral innate response, and expression of TMPRSS genes. By doing this, we found both pSARS2 and the field delta variant viruses upregulated type I interferon and innate antiviral responses in the infected NHBE and HSAEC cells compared to their uninfected controls. However, we did not observe significant upregulation in the tissue factor transcription in both pSARS2 and the delta variant infected samples.
2023-09-11 | GSE242722 | GEO
Project description:SARS-CoV-2 infects epithelial cells of the human gastrointestinal (GI) tract and causes related symptoms. HIV infection impairs gut homeostasis and is associated with an increased risk of COVID-19 fatality. To investigate the potential link between these observations, we analyzed single-cell transcriptional profiles and SARS-CoV-2 entry receptor expression across lymphoid and mucosal human tissue from chronically HIV-infected individuals and uninfected controls. Absorptive gut enterocytes displayed the highest coexpression of SARS-CoV-2 receptors ACE2, TMPRSS2, and TMPRSS4, of which ACE2 expression was associated with canonical interferon response and antiviral genes. Chronic treated HIV infection was associated with a clear antiviral response in gut enterocytes and, unexpectedly, with a substantial reduction of ACE2 and TMPRSS2 target cells. Gut tissue from SARS-CoV-2–infected individuals, however, showed abundant SARS-CoV-2 nucleocapsid protein in both the large and small intestine, including an HIV-coinfected individual. Thus, upregulation of antiviral response genes and downregulation of ACE2 and TMPRSS2 in the GI tract of HIV-infected individuals does not prevent SARS-CoV-2 infection in this compartment. The impact of these HIV-associated intestinal mucosal changes on SARS-CoV-2 infection dynamics, disease severity, and vaccine responses remains unclear and requires further investigation.
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