IL-6: Relevance for immunopathology of SARS-CoV-2.
Ontology highlight
ABSTRACT:
SUBMITTER: Gubernatorova EO
PROVIDER: S-EPMC7237916 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Coronaviruses are a group of enveloped RNA viruses that are diversely found in humans and now declared a global pandemic by the World Health Organization in March 2020. The population's susceptibility to these highly pathogenic coronaviruses has contributed to large outbreaks, evolved into public health events, and rapidly transmitted globally. Thus, there is an urgent need to develop effective therapies and vaccines against this disease. In the primary stage of severe acute respiratory syndrome coronavirus (SARS-COV-2) infection, the signs and symptoms are nonspecific, and many more cases have been observed than initially expected. Genome sequencing is performed regularly to identify genetic changes to SARS-COV-2, and vaccine development is focused on manufacture, production, and based on specific problems, and very few are available on recent developments in the prevention of outbreaks. The aim of this review article to explore recent updates on SARS-COV-2 in the context of pathogenesis during disease progression, and innate acquired mechanisms of defense, This includes advances in diagnostics, susceptibility, and severity of host-virus genome interactions, modes of transmission, active compounds being used in pre-clinical and clinical trials for the treatment of patients, vaccine developments, and the effectiveness of SARS-COV-2 prevention and control measures. We have summarized the importance of pathophysiology immune response, Diagnostics, vaccine development currently approaches explored for SARS-COV-2.
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Project description:RNA-seq analysis was performed to understand the role of type I IFN response during SARS CoV-2 infection using transgenic mice. Each sample was collected from an individual C57BL/6J mouse. The total RNA was extracted from uninfected and SARS-CoV-2 infected mice lung tissue using RNeasy mini kit (QIAGEN #74104). The quantity of RNA was determined using Qubit RNA assay kit with Qubit 4.0 and the quality of RNA was tested using agarose gel electrophoresis and High Sensitivity Tape station Kit (Agilent 2200, #5067-5576, #5067-5577 and #5067-5578). After assessing the quality of RNA, ~900 ng of total RNA was taken for library preparation using NEBNext®Ultra™ II Directional RNA Library kit for Illumina (# E7760L) and NEBNext Poly (A) mRNA Magnetic Isolation Module (# E7490L) as per manufacturer's protocol. The prepared library was quantified using Qubit dsDNA assay kit (Invitrogen, Q32851) followed by quality check (QC) and fragment size distribution using a High Sensitivity Tape station Kit (Agilent 2200, #5067-5584 and #5067-5585). The library was sequenced using the HiSeq 4000 Illumina platform. The paired-end (PE) reads quality checks for each sample were carried out using FastQC v.0.11.5 (http://www.bioinformatics.babraham.ac.uk/projects/fastqc/). The adapter sequence was trimmed using the BBDuk version 37.58 version 37.58 and the alignment was performed using STAR v.2.5.3a with default parameters with human hg38 genome build, gencode v21 gtf 9GRCh38) from the gencode. The duplicates were discarded using Picard-2.9.4 (https://broadinstitute.github.io/picard/) from the aligned bam files and read counts were generated using featureCount v.1.5.3 from subread-1.5.3 package (https://bioinf.wehi.edu.au/) with Q = 10 for mapping quality. The count files were used as input for downstream differential gene expression analysis with DESeq2 version 1.14.1 9. The genes with read counts of ≤ 10 in any comparison were discarded followed by count transformation and statistical analysis using DESeq “R”. The “P” value were adjusted using the Benjamini and Hochberg multiple testing correction and the differentially expressed genes were identified (fold change of ≥1.5, P-value < 0.05). A unified non-redundant gene list was made for different comparisons and subjected to gene ontology (GO) analysis using the reactome database (https://reactome.org/). The top pathways (p < 0.05) were used for generating heat maps using Complexheatmap (Version 2.0.0) through unsupervised hierarchical clustering. The expression clusters were annotated based on enriched GO terms. Normalized gene expression was used to generate the boxplots with a median depicting the trends in the expression across the different conditions using ggplot2 [version 3.3.5]. The pathways analysis was performed using Metascape database (https://metascape.org/gp/index.html#/main/step1). The top pathways (p < 0.05) were taken for constructing bubble plots using ggplot2 [version 3.3.5].
2023-12-29 | E-MTAB-12681 | biostudies-arrayexpress
Project description:BackgroundThe release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear.ObjectivesWe aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19.MethodsWe performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection.ResultsWe found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage.ConclusionThese results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy.
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Project description:Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here we uncover a role of the complement system in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonizes SARS-CoV-2 particles via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently induces type-I interferon and pro-inflammatory cytokine responses via activation of dendritic cells, which are inhibited by antibodies against the complement receptors (CR) 3 and 4. Serum from COVID-19 patients, or monoclonal antibodies against SARS-CoV-2, attenuate innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking of CD32, the FcγRII antibody receptor of dendritic cells, restores complement-induced immunity. These results suggest that opsonization of SARS-CoV-2 by complement is involved in the induction of innate and adaptive immunity to SARS-CoV-2 in the acute phase of infection. Subsequent antibody responses limit inflammation and restore immune homeostasis. These findings suggest that dysregulation of the complement system and FcγRII signaling may contribute to severe COVID-19.
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Project description:The recent pandemic we are experiencing caused by the coronavirus disease 2019 (COVID-19) has put the world's population on the rack, with more than 191 million cases and more than 4.1 million deaths confirmed to date. This disease is caused by a new type of coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A massive proteomic analysis has revealed that one of the structural proteins of the virus, the E protein, interacts with BRD2 and BRD4 proteins of the Bromodomain and Extra Terminal domain (BET) family of proteins. BETs are essential to cell cycle progression, inflammation and immune response and have also been strongly associated with infection by different types of viruses. The fundamental role BET proteins play in transcription makes them appropriate targets for the propagation strategies of some viruses. Recognition of histone acetylation by BET bromodomains is essential for transcription control. The development of drugs mimicking acetyl groups, and thereby able to displace BET proteins from chromatin, has boosted interest on BETs as attractive targets for therapeutic intervention. The success of these drugs against a variety of diseases in cellular and animal models has been recently enlarged with promising results from SARS-CoV-2 infection studies.
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Project description:The incidence and case-fatality rates (CFRs) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, the etiological agent for Coronavirus Disease 2019 (COVID-19), have been rising unabated. Even though the entire world has been implementing infection prevention and control measures, the pandemic continues to spread. It has been widely accepted that preventive vaccination strategies are the public health measures for countering this pandemic. This study critically reviews the latest scientific advancement in genomics, replication pattern, pathogenesis, and immunopathology of SARS-CoV-2 infection and how these concepts could be used in the development of vaccines. We also offer a detailed discussion on the anticipated potency, efficacy, safety, and pharmaco-economic issues that are and will be associated with candidate COVID-19 vaccines.
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Project description:HAE cultures were infected with SARS-CoV, SARS-dORF6 or SARS-BatSRBD and were directly compared to A/CA/04/2009 H1N1 influenza-infected cultures. Cell samples were collected at various hours post-infection for analysis. Time Points = 0, 12, 24, 36, 48, 60, 72, 84 and 96 hrs post-infection for SARS-CoV, SARS-dORF6 and SARS-BatSRBD. Time Points = 0, 6, 12, 18, 24, 36 and 48 hrs post-infection for H1N1. Done in triplicate or quadruplicate for RNA Triplicates/quadruplicates are defined as 3/4 different wells, plated at the same time and using the same cell stock for all replicates. Time matched mocks done in triplicate from same cell stock as rest of samples. Culture medium (the same as what the virus stock is in) will be used for the mock infections. Infection was done at an MOI of 2.
2013-07-31 | E-GEOD-47960 | biostudies-arrayexpress