Host transcriptional response to SARS-CoV-2 infection in COVID-19 patients.
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ABSTRACT:
SUBMITTER: Singh NK
PROVIDER: S-EPMC8453261 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background & aimsGiven that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance.MethodsHuman intestinal biopsy tissues were obtained from patients with COVID-19 (n = 19) and uninfected control individuals (n = 10) for microscopic examination, cytometry by time of flight analyses, and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in 2 large, independent cohorts of hospitalized patients in the United States (N = 634) and Europe (N = 287) using multivariate logistic regressions.ResultsCOVID-19 case patients and control individuals in the biopsy cohort were comparable for age, sex, rates of hospitalization, and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy in 15 of 17 patients studied. High-dimensional analyses of GI tissues showed low levels of inflammation, including down-regulation of key inflammatory genes including IFNG, CXCL8, CXCL2, and IL1B and reduced frequencies of proinflammatory dendritic cells compared with control individuals. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of sex, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms.ConclusionsThese data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in patients with COVID-19 presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2-associated inflammation needs to be further examined.
| S-EPMC7931673 | biostudies-literature
Project description:ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2; the GLK-induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID-19 cohort. Remarkably, SARS-CoV-2 spike protein stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to dissociation of ACE2 from its E3 ligase UBR4. Reduction of UBR4-induced Lys48-linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS-CoV-2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, as well as ACE2-containing exosomes. Collectively, ACE2 stabilization by SARS-CoV-2-induced MAP4K3/GLK may contribute to the pathogenesis of COVID-19.
| S-SCDT-EMM-2022-15904 | biostudies-other
Project description: Not available
| S-BSST955 | biostudies-other
Project description:SARS-CoV-2 is a beta coronavirus causing COVID-19 which first emerged in Wuhan, China and was later declared a pandemic by the World Health Organization. Since then the economical, health and human cost has been enormous for the world. However, little work has been done to understand the transcriptional changes brought about by the virus in human hosts. We have compared COVID-19 positive samples with negative samples from Indian patients to better understand the host response.. We find many genes related to immune response up-regulated in the COVID-19 patients. Many of these are the usual response genes against the viral infection but type I interferon appears to be a key immune response activated against SARS-CoV-2. A large number of the differentially expressed genes were down-regulated pointing towards translational arrest and down regulation of host mRNA during late infection. The down-regulated genes are well correlated with the clinical manifestations and symptoms due to SARS-CoV-2 infection such as the loss of smell and taste. We also find evidence of altered gene expression profiles associated with systemic complications such as neurological disturbances and high insulin requirement. Finally, we have identified many lncRNAs being down-regulated during COVID-19 infections. A few of these lncRNAs have functional role in viral infection. However, to understand the functional role of other lncRNAs, we looked at the function of their closest gene, since lncRNA are believed to have cis functionality. Our analysis suggests a role for lncRNA in down-regulation of metabolic and developmental processes during COVID-19 infection.
2021-08-01 | GSE166530 | GEO
Project description:SARS-CoV-2 can generate viral microRNAs (v-miRNAs) that target host gene expression. This study used small RNAseq to identify the v-miRNAs present in COVID-19 patients' nasopharyngeal swabs. The study identified a specific conserved v-miRNA sequence (CoV2-miR-O8) unique to SARS-CoV-2 that is highly present in COVID-19 patients' samples, interacts with Argonaute, and has features consistent with Dicer and Drosha generation. CoV2-miR-O8 is predicted to target specific human genes and can be detected by RTPCR assays in patients.
2023-12-11 | GSE230080 | GEO
Project description:Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
| S-EPMC7227586 | biostudies-literature
Project description:A common trait among RNA viruses is their high capability to acquire genetic variability due to viral and host mechanisms. Next-generation sequencing (NGS) analysis enables the deep study of the viral quasispecies in samples from infected individuals. In this study, the viral quasispecies complexity and single nucleotide polymorphisms of the SARS-CoV-2 spike gene of coronavirus disease 2019 (COVID-19) patients with mild or severe disease were investigated using next-generation sequencing (Illumina platform). SARS-CoV-2 spike variability was higher in patients with long-lasting infection. Most substitutions found were present at frequencies lower than 1%, and had an A → G or T → C pattern, consistent with variants caused by adenosine deaminase acting on RNA-1 (ADAR1). ADAR1 affected a small fraction of replicating genomes, but produced multiple, mainly non-synonymous mutations. ADAR1 editing during replication rather than the RNA-dependent RNA polymerase (nsp12) was the predominant mechanism generating SARS-CoV-2 genetic variability. However, the mutations produced are not fixed in the infected human population, suggesting that ADAR1 may have an antiviral role, whereas nsp12-induced mutations occurring in patients with high viremia and persistent infection are the main source of new SARS-CoV-2 variants.
| S-EPMC8425778 | biostudies-literature
Project description:BackgroundThe Coronavirus Disease 2019 (COVID-19) pandemic has infected over 10 million people globally with a relatively high mortality rate. There are many therapeutics undergoing clinical trials, but there is no effective vaccine or therapy for treatment thus far. After affected by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), molecular signaling pathways of host cells play critical roles during the life cycle of SARS-CoV-2. Thus, it is significant to identify the involved molecular signaling pathways within the host cells. Drugs targeting these molecular signaling pathways could be potentially effective for COVID-19 treatment.MethodsIn this study, we developed a novel integrative analysis approach to identify the related molecular signaling pathways within host cells, and repurposed drugs as potentially effective treatments for COVID-19, based on the transcriptional response of host cells.ResultsWe identified activated signaling pathways associated with the infection caused SARS-CoV-2 in human lung epithelial cells through integrative analysis. Then, the activated gene ontologies (GOs) and super GOs were identified. Signaling pathways and GOs such as MAPK, JNK, STAT, ERK, JAK-STAT, IRF7-NFkB signaling, and MYD88/CXCR6 immune signaling were particularly activated. Based on the identified signaling pathways and GOs, a set of potentially effective drugs were repurposed by integrating the drug-target and reverse gene expression data resources. In addition to many drugs being evaluated in clinical trials, the dexamethasone was top-ranked in the prediction, which was the first reported drug to be able to significantly reduce the death rate of COVID-19 patients receiving respiratory support.ConclusionsThe integrative genomics data analysis and results can be helpful to understand the associated molecular signaling pathways within host cells, and facilitate the discovery of effective drugs for COVID-19 treatment.
| S-EPMC7789899 | biostudies-literature
Project description:COVID-19 is a lurking calamitous disease caused by an unusual virus, SARS-CoV-2, causing massive deaths worldwide. Nonetheless, explicit therapeutic drugs or clinically approved vaccines are not available for COVID-19. Thus, a comprehensive research is crucially needed to decode the pathogenic tools, plausible drug targets, committed to the development of efficient therapy. Host-pathogen interactions via host cellular components is an emerging field of research in this respect. miRNAs have been established as vital players in host-virus interactions. Moreover, viruses have the capability to manoeuvre the host miRNA networks according to their own obligations. Besides protein coding mRNAs, noncoding RNAs might also be targeted in infected cells and viruses can exploit the host miRNA network via ceRNA effect. We have predicted a ceRNA network involving one miRNA (miR-124-3p), one mRNA (Ddx58), one lncRNA (Gm26917) and two circRNAs (Ppp1r10, C330019G07RiK) in SARS-CoV infected cells. We have identified 4 DEGs-Isg15, Ddx58, Oasl1, Usp18 by analyzing a mRNA GEO dataset. There is no notable induction of IFNs and IFN-induced ACE2, significant receptor responsible for S-protein binding mediated viral entry. Pathway enrichment and GO analysis conceded the enrichment of pathways associated with interferon signalling and antiviral-mechanism by IFN-stimulated genes. Further, we have identified 3 noncoding RNAs, playing as potential ceRNAs to the genes associated with immune mechanisms. This integrative analysis has identified noncoding RNAs and their plausible targets, which could effectively enhance the understanding of molecular mechanisms associated with viral infection. However, validation of these targets is further corroborated to determine their therapeutic efficacy.
| S-EPMC7428439 | biostudies-literature
Project description:Healthcare workers were recruited at St Bartholomew’s Hospital, London, UK in the week of lockdown in the United Kingdom (between 23rd and 31st March 2020). Participants underwent weekly evaluation using a questionnaire and biological sample collection (including serological assays) for up to 16 weeks when attending for work and self-declared as fit to attend work at each visit, with further follow up samples collected at 24 weeks. Blood RNA sequencing data was to be used to identify host-response biomarkers of early SARS-CoV-2 infection, to evaluate existing blood transcriptomic signatures of viral infection, and to describe the underlying biology during SARS-CoV-2 infection. This submission includes a total of 172 blood RNA samples from 99 participants. Of these, 114 samples (including 16 convalescent samples collected 6 months after infection) were obtained from 41 SARS-CoV-2 cases, with the remaining 58 from uninfected controls. Participants with available blood RNA samples who had PCR-confirmed SARS-CoV-2 infection during follow-up were included as ‘cases’. Those without evidence of SARS-CoV-2 infection on nasopharyngeal swabs and who remained seronegative by both Euroimmun anti S1 spike protein and Roche anti nucleocapsid protein throughout follow-up were included as uninfected controls. ‘Cases’ include all available RNA samples, including convalescent samples at week 24 of follow-up for a subset of participants. For uninfected controls, we included baseline samples only. Sample class denotes weekly interval to positive SARS-CoV-2 PCR; non-infected controls (NIC); convalescent samples (Conv)_.
2021-07-07 | E-MTAB-10022 | biostudies-arrayexpress