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1.
Genes (Basel) ; 13(1)2021 12 23.
Article in English | MEDLINE | ID: covidwho-1580896

ABSTRACT

ADAR1-mediated deamination of adenosines in long double-stranded RNAs plays an important role in modulating the innate immune response. However, recent investigations based on metatranscriptomic samples of COVID-19 patients and SARS-COV-2-infected Vero cells have recovered contrasting findings. Using RNAseq data from time course experiments of infected human cell lines and transcriptome data from Vero cells and clinical samples, we prove that A-to-G changes observed in SARS-COV-2 genomes represent genuine RNA editing events, likely mediated by ADAR1. While the A-to-I editing rate is generally low, changes are distributed along the entire viral genome, are overrepresented in exonic regions, and are (in the majority of cases) nonsynonymous. The impact of RNA editing on virus-host interactions could be relevant to identify potential targets for therapeutic interventions.


Subject(s)
Adenosine Deaminase/genetics , COVID-19/genetics , Genome, Viral , Host-Pathogen Interactions/genetics , RNA Editing , RNA, Viral/genetics , RNA-Binding Proteins/genetics , SARS-CoV-2/genetics , Adenosine/metabolism , Adenosine Deaminase/immunology , Animals , COVID-19/metabolism , COVID-19/virology , Cell Line, Tumor , Chlorocebus aethiops , DEAD Box Protein 58/genetics , DEAD Box Protein 58/immunology , Deamination , Epithelial Cells/immunology , Epithelial Cells/virology , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate , Inosine/metabolism , Interferon-Induced Helicase, IFIH1/genetics , Interferon-Induced Helicase, IFIH1/immunology , Interferon-beta/genetics , Interferon-beta/immunology , RNA, Double-Stranded/genetics , RNA, Double-Stranded/immunology , RNA, Viral/immunology , RNA-Binding Proteins/immunology , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Transcriptome , Vero Cells
2.
J Immunol ; 206(8): 1691-1696, 2021 04 15.
Article in English | MEDLINE | ID: covidwho-1158408

ABSTRACT

Severe COVID-19 disease is associated with elevated inflammatory responses. One form of Aicardi-Goutières syndrome caused by inactivating mutations in ADAR results in reduced adenosine-to-inosine (A-to-I) editing of endogenous dsRNAs, induction of IFNs, IFN-stimulated genes, other inflammatory mediators, morbidity, and mortality. Alu elements, ∼10% of the human genome, are the most common A-to-I-editing sites. Using leukocyte whole-genome RNA-sequencing data, we found reduced A-to-I editing of Alu dsRNAs in patients with severe COVID-19 disease. Dendritic cells infected with COVID-19 also exhibit reduced A-to-I editing of Alu dsRNAs. Unedited Alu dsRNAs, but not edited Alu dsRNAs, are potent inducers of IRF and NF-κB transcriptional responses, IL6, IL8, and IFN-stimulated genes. Thus, decreased A-to-I editing that may lead to accumulation of unedited Alu dsRNAs and increased inflammatory responses is associated with severe COVID-19 disease.


Subject(s)
Adenosine/genetics , Alu Elements/genetics , COVID-19/genetics , Inosine/genetics , RNA Editing/genetics , RNA, Double-Stranded/genetics , SARS-CoV-2 , Severity of Illness Index , Adenosine/metabolism , COVID-19/pathology , Dendritic Cells/metabolism , Dendritic Cells/virology , Genome, Human , Humans , Inosine/metabolism , Interferon Regulatory Factors/metabolism , NF-kappa B/metabolism , RNA-Seq , Signal Transduction/genetics
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