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Updated: Nov 11, 2025
A Nonsequencing Approach for the Rapid Detection of RNA Editing
Published on: April 21, 2022
Cutting Edge: Reduced Adenosine-to-Inosine Editing of Endogenous Alu RNAs in Severe COVID-19 Disease
Philip S Crooke1, John T Tossberg2, Krislyn P Porter2
1Department of Mathematics, Vanderbilt University, Nashville, TN 37212.
Insights
Reduced adenosine-to-inosine (A-to-I) editing of Alu dsRNAs is linked to severe COVID-19. This decrease may cause unedited Alu dsRNAs to trigger inflammatory responses, contributing to disease severity.
Area of Science:
- Molecular Biology
- Immunology
- Genetics
Background:
- Severe COVID-19 involves heightened inflammatory responses.
- Aicardi-Goutières syndrome, linked to ADAR mutations, shows reduced RNA editing and inflammation.
- Alu elements are major sites for adenosine-to-inosine (A-to-I) RNA editing.
Purpose of the Study:
- To investigate the role of A-to-I editing of Alu dsRNAs in severe COVID-19.
- To determine if reduced Alu editing contributes to inflammatory responses in COVID-19.
Main Methods:
- Whole-genome RNA sequencing of leukocytes from COVID-19 patients.
- Analysis of A-to-I editing levels in Alu dsRNAs.
- In vitro studies using dendritic cells infected with SARS-CoV-2.
Main Results:
- Patients with severe COVID-19 exhibited reduced A-to-I editing of Alu dsRNAs.
- Dendritic cells infected with SARS-CoV-2 also showed decreased Alu dsRNA editing.
- Unedited Alu dsRNAs, but not edited ones, potently induced inflammatory gene expression (IRF, NF-κB, IL6, IL8, ISGs).
Conclusions:
- Decreased A-to-I editing of Alu dsRNAs is associated with severe COVID-19.
- Accumulation of unedited Alu dsRNAs may drive inflammatory responses, contributing to COVID-19 severity.
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.
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