Boson HCV infected liver bulk RNASeq study
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ABSTRACT:
PROVIDER: EGAS00001004996 | EGA |
REPOSITORIES: EGA
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Project description:SARS-CoV-2, the agent causing COVID-19, invades epithelial cells, including those of the respiratory and gastrointestinal mucosa, using angiotensin-converting enzyme-2 (ACE2) as a receptor. Subsequent inflammation can promote rapid virus clearance. However, severe cases of COVID-19 are characterized by an inefficient immune response that fails to clear infection. Using primary epithelial organoids from the colon, we explored how IFN-γ, a central antiviral mediator elevated in COVID-19, affects differentiation, ACE2 expression, and infectivity with SARS-CoV-2. ACE2 is mainly expressed by surface enterocytes of mouse and human colon. Inducing enterocyte differentiation in organoid culture resulted in increased ACE2 production. IFN-γ treatment promoted differentiation into mature KRT20+ enterocytes expressing high levels of ACE2. Similarly, IFN-γ promoted expression of ACE2 in human primary lung cells. IFN-y driven differentiation increased susceptibility to SARS-CoV-2 infection and electron microscopy revealed that the virus can efficiently complete its full life cycle in IFN-γ-treated enterocytes. Furthermore, infection-induced epithelial interferon signaling promoted enterocyte maturation and enhanced ACE2 expression. We reveal a mechanism by which IFN-y-driven inflammatory responses may increase susceptibility to SARS-CoV-2 and promote its replication.
2021-01-01 | GSE156544 | GEO
Project description:Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. HCV can be sensed by host innate immunity to induce expression of interferons (IFNs) and a number of antiviral effectors. HCV-encoded NS3/4 serine protease can subvert host innate immune responses by cleaving MAVS, a critical adaptor protein in the RLR-mediated IFN signaling. To study innate immunity in the context of HCV infection, we constructed Huh7-MAVSR cells which express a mutant MAVS resistant to NS3/4A cleavage. HCV infection induces robust IFN response in Huh7-MAVSR cells, providing a cellular system to study antiviral innate immune response against HCV infection. To analyze host innate antiviral effectors against HCV infection, we performed an mRNA microarray analysis in the HCV-infected Huh7-MAVSR cells.
2018-02-08 | GSE110312 | GEO
Project description:In this model, TLR2-TLR6 mediates MyD88 pathway gets activated, which activates IL-12 production and induces iNOS expression when the Macrophage is infected with Leishmania parasite. The early induction of IL-10 takes place which leads to the induction of NFIL3, HDAC3, and SHP-1. They inhibit IL-12 production and thus hamper IL-12 induced IFN-gamma mediated; Nitric oxide production. A key transcription factor NFAT5 connects IL-12 and IL-10 pathways. It upregulates IL-12 and downregulates IL-10. In this model, NFAT5 is downregulated which is also inhibiting IL-12.
2022-01-24 | MODEL2012040002 | BioModels
Project description:BackgroundDespite direct-acting antivirals (DAA), aims to "eradicate" viral hepatitis by 2030 remain unlikely. In Nepal, an expert consortium was established to treat HCV through Nepal earthquakes aftermath offering a model for HCV treatment expansion in a resource-poor setting.Methodology/principal findingsIn 2015, we established a network of hepatologists, laboratory experts, and community-based leaders at 6 Opioid Substitution Treatment (OST) sites from 4 cities in Nepal screening 838 patients for a treatment cohort of 600 individuals with HCV infection and past or current drug use. During phase 1, patients were treated with interferon-based regimens (n = 46). During phase 2, 135 patients with optimal predictors (HIV controlled, without cirrhosis, low baseline HCV viral load) were treated with DAA-based regimens. During phase 3, IFN-free DAA treatment was expanded, regardless of HCV disease severity, HIV viremia or drug use. Sustained virologic response (SVR) was assessed at 12 weeks. Median age was 37 years and 95.5% were males. HCV genotype was 3 (53.2%) or 1a (40.7%) and 32% had cirrhosis; 42.5% were HIV-HCV coinfected. The intention-to-treat (ITT) SVR rates in phase 2 and 3 were 97% and 81%, respectively. The overall per-protocol and ITT SVR rates were 97% and 85%, respectively. By multivariable analysis, treatment at the Kathmandu site was protective and substance use, treatment during phase 3 were associated with failure to achieve SVR.Conclusions/significanceVery high SVR rates may be achieved in a difficult-to-treat, low-income population whatever the patient's profile and disease severity. The excellent treatment outcomes observed in this real-life community study should prompt further HCV treatment initiatives in Nepal.
| S-EPMC7773414 | biostudies-literature
Project description:BackgroundImmune biomarkers are implicated in HCV treatment response, fibrosis, and accelerated pathogenesis of comorbidities, though only D-dimer and C-reactive protein have been consistently studied. Few studies have evaluated HIV/HCV co-infection, and little longitudinal data exists describing a broader antiviral cytokine response.MethodsFifty immune biomarkers were analyzed at baseline (BL) and HCV end of treatment follow-up(FU) time point using the Luminex 50-plex assay in plasma samples from 15 HCV-cleared, 24 HCV mono- and 49 HIV/HCV co-infected patients receiving antiretroviral treatment, who either did or did not receive pegylated-interferon/ribavirin HCV treatment. Biomarker levels were compared among spontaneous clearance patients, mono- and co-infected, untreated and HCV-treated, and sustained virologic responders (SVR) and non-responders (NR) at BL and FU using nonparametric analyses. A Bonferroni correction, adjusting for tests of 50 biomarkers, was used to reduce Type I error.ResultsCompared to HCV patients at BL, HIV/HCV patients had 22 significantly higher and 4 significantly lower biomarker levels, following correction for multiple testing. There were no significantly different BL levels when comparing SVR and NR in mono- or co-infected patients; however, FU levels changed considerably in co-infected patients, with seven becoming significantly higher and eight becoming significantly lower in SVR patients. Longitudinally between BL and FU, 13 markers significantly changed in co-infected SVR patients, while none significantly changed in co-infected NR patients. There were also no significant changes in longitudinal analyses of mono-infected patients achieving SVR or mono-infected and co-infected groups deferring treatment.ConclusionsClear differences exist in pattern and quantity of plasma immune biomarkers among HCV mono-infected, HIV/HCV co-infected, and HCV-cleared patients; and with SVR in co-infected patients treated for HCV. Though >90% of patients were male and co-infected had a larger percentage of African American patients, our findings may have implications for better understanding HCV pathogenesis, treatment outcomes, and future therapeutic targets.
| S-EPMC3617231 | biostudies-literature
Project description:Type III interferon, also known as interferon lambda (IFN-λ), is the newest addition to the IFN family. IFN-λ is primarily produced by the airway epithelium and curbs viral infections without triggering systemic pro-inflammatory cytokine responses1. Of the current IFN COVID-19 trials (as of 6/27/2020), four propose the use of IFN-λ. However, it remains to be determined whether IFN-λ induces ACE2 expression in the human airway epithelium.
2020-12-31 | GSE153428 | GEO
Project description:Ace2 transcription factor family genes are found in many fungal genomes and are required for regulation of expression of genes involved in cell separation. We used transcriptional profiling to identify the targets of Ace2 in Candida albicans, and we show that these include several cell wall components, such as glucanases and glycosylphosphatidylinositol-anchored proteins. Expression is downregulated in ace2 deletion mutants in both yeast and hyphal cells. In addition, deleting ace2 results in dramatic changes in expression of metabolic pathways. Expression of glycolytic enzymes is reduced, while expression of respiratory genes (including those involved in the tricarboxylic acid cycle, oxidative phosphorylation, and ATP synthesis) is increased. Similar changes occur in both yeast and hyphal cells. In contrast, genes required for acetyl-coenzyme A and lipid metabolism are upregulated in an ace2 deletion mutant grown predominantly as yeast cells but are downregulated in hyphae. These results suggest that in wild-type strains, Ace2 acts to increase glycolysis and reduce respiration. This is supported by the observation that deleting ace2 results in increased resistance to antimycin A, a drug that inhibits respiration. We also show that Ace2 is required for filamentation in response to low oxygen concentrations (hypoxia). We suggest that filamentation is induced in wild-type cells by reducing respiration (using low oxygen or respiratory drugs) and that mutants with increased respiratory activity fail to undergo filamentation under these conditions. This SuperSeries is composed of the SubSeries listed below.
2007-02-23 | GSE7105 | GEO
Project description:In this study a gene expression (i.e., RNAseq) analysis was performed in HEK293T-ACE2 cellular model upon infection with viral particle belonging to VOC Delta (MOI: 0.026) for 24 hours in order to have a global picture of the transcriptome landscape in response to early phase of infection of SARS-CoV-2 ( VOC Delta infection and to evaluate the role of Ca2+ in HEK293-ACE2 cellular model and transfer to homeostasis in SARS-COV-2 patients (by Pasqualino de Antonellis1-2* and Veronica Ferrucci 1-2* (first authors) et al. and Massimo Zollo1-2# (corresponding author). Manuscript in preparation 2022 July 15th 2022. Short title "ATP2B1 (PMCA1), regulated by FOXO3, influences susceptibility to severe COVID19".
2022-12-01 | E-MTAB-11973 | biostudies-arrayexpress
Project description:Phenotypic and immunogenetic characteristics of NK cells have been recently associated with treatment outcome of HCV infected patients. However, thus far, no global NK patterns predictive of response to antiviral therapy in HCV infection have been identified. We here analyzed phenotypic and transcriptional characteristics of NK cells derived from prospectively followed patients with chronic HCV infection prior to treatment with PEG-IFN/RBV. The results report that the pre-treatment transcriptional patterns of purified NK cells from patients subsequently undergoing a sustained virologic response (SVR) clearly segregated from those of non-responder (NR) patients and surprisingly overlapped with the genomic profile of NK cells from healthy donors and from patients who spontaneously cleared the virus (SR). The treatment outcome was associated with differential surface expression of NKp30 and NKG2D and with the transcriptional expression of molecules involved in post-transcriptional modifications of RNA/protein trafficking and HLA class II signaling. With the development of a highly stringent prediction model (LOOCV p value < 0.00001) we identified a 33 gene signature whose expression predicted with 100% accuracy the outcome of IFN based treatment. None of the genes found to differentiate patients with SVR from NR were related to the IL28B polymorphism. Neither an IL28B CC homozygosis was significantly and clearly associated with SVR in our series of patients. Thus, NK cells are associated to different HCV disease courses and response to treatment and the NK cell evaluation in HCV patients might provide a comprehensive explanation of useful determinants of clinical response in HCV-infected patients subjected to treatment regimens that have IFN as their backbone.
2015-10-01 | GSE51941 | GEO
Project description:The SARS-CoV-2 pandemic has resulted in widespread morbidity and mortality globally, but with widely variable outcomes. The development of severe disease and mortality is higher in older individuals, males and those with other co-morbidities, and may vary across ethnic groups. However, so far, no host genetic factor has been clearly associated with susceptibility and development of severe disease. To understand the impact of host genetics on expression of ACE2 (SARS-CoV-2 receptor) during RNA virus infection we performed a GWAS for ACE2 expression in HCV-infected liver tissue from 195 individuals. We discovered that polymorphisms in the host IFNL region which control expression of IFNL3 and IFNL4 modulate ACE2 expression. ACE2 expression was regulated additionally by age, with a subsidiary effect of co-morbidity. The IFNL locus controlled expression of a gene network incorporating many well-known interferon-stimulated genes which anti-correlated with ACE2 transcript levels. The same anti-correlation was found in the gastrointestinal tract, a site of SARS-CoV-2 replication where inflammation driven interferon-stimulated genes are negatively correlated with ACE2 expression. The interferon dependent regulation of ACE2 was identified in a murine model of SARS-CoV-1 suggesting conserved regulation of ACE2 across species. Polymorphisms in the IFNL region, as well as age, may impact not only on classical antiviral responses but also on ACE2 with potential consequences for clinical outcomes in distinct ethnic groups and with implications for therapeutic interventions.
2020-04-30 | GSE149601 | GEO