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2.
PLoS Genet ; 18(3): e1010130, 2022 03.
Article in English | MEDLINE | ID: covidwho-1770640

ABSTRACT

SARS-CoV-2 is a positive-sense, single-stranded RNA virus responsible for the COVID-19 pandemic. It remains unclear whether and to what extent the virus in human host cells undergoes RNA editing, a major RNA modification mechanism. Here we perform a robust bioinformatic analysis of metatranscriptomic data from multiple bronchoalveolar lavage fluid samples of COVID-19 patients, revealing an appreciable number of A-to-I RNA editing candidate sites in SARS-CoV-2. We confirm the enrichment of A-to-I RNA editing signals at these candidate sites through evaluating four characteristics specific to RNA editing: the inferred RNA editing sites exhibit (i) stronger ADAR1 binding affinity predicted by a deep-learning model built from ADAR1 CLIP-seq data, (ii) decreased editing levels in ADAR1-inhibited human lung cells, (iii) local clustering patterns, and (iv) higher RNA secondary structure propensity. Our results have critical implications in understanding the evolution of SARS-CoV-2 as well as in COVID-19 research, such as phylogenetic analysis and vaccine development.


Subject(s)
COVID-19 , SARS-CoV-2 , Adenosine Deaminase/metabolism , COVID-19/genetics , Humans , Nucleotides/metabolism , Pandemics , Phylogeny , RNA/metabolism , RNA Editing/genetics , SARS-CoV-2/genetics
3.
J Appl Genet ; 63(2): 423-428, 2022 May.
Article in English | MEDLINE | ID: covidwho-1739445

ABSTRACT

Analysis of the SARS-CoV-2 transcriptome has revealed a background of low-frequency intra-host genetic changes with a strong bias towards transitions. A similar pattern is also observed when inter-host variability is considered. We and others have shown that the cellular RNA editing machinery based on ADAR and APOBEC host-deaminases could be involved in the onset of SARS-CoV-2 genetic variability. Our hypothesis is based both on similarities with other known forms of viral genome editing and on the excess of transition changes, which is difficult to explain with errors during viral replication. Zong et al. criticize our analysis on both conceptual and technical grounds. While ultimate proof of an involvement of host deaminases in viral RNA editing will depend on experimental validation, here, we address the criticism to suggest that viral RNA editing is the most reasonable explanation for the observed intra- and inter-host variability.


Subject(s)
COVID-19 , RNA Editing , Adenosine Deaminase/genetics , Adenosine Deaminase/metabolism , COVID-19/genetics , Humans , RNA Editing/genetics , SARS-CoV-2/genetics , Transcriptome/genetics
4.
Nucleic Acids Res ; 50(5): 2509-2521, 2022 03 21.
Article in English | MEDLINE | ID: covidwho-1722548

ABSTRACT

Upon SARS-CoV-2 infection, viral intermediates specifically activate the IFN response through MDA5-mediated sensing and accordingly induce ADAR1 p150 expression, which might lead to viral A-to-I RNA editing. Here, we developed an RNA virus-specific editing identification pipeline, surveyed 7622 RNA-seq data from diverse types of samples infected with SARS-CoV-2, and constructed an atlas of A-to-I RNA editing sites in SARS-CoV-2. We found that A-to-I editing was dynamically regulated, varied between tissue and cell types, and was correlated with the intensity of innate immune response. On average, 91 editing events were deposited at viral dsRNA intermediates per sample. Moreover, editing hotspots were observed, including recoding sites in the spike gene that affect viral infectivity and antigenicity. Finally, we provided evidence that RNA editing accelerated SARS-CoV-2 evolution in humans during the epidemic. Our study highlights the ability of SARS-CoV-2 to hijack components of the host antiviral machinery to edit its genome and fuel its evolution, and also provides a framework and resource for studying viral RNA editing.


Subject(s)
COVID-19/immunology , Immunity, Innate/immunology , RNA Editing/immunology , SARS-CoV-2/immunology , Adenosine Deaminase/genetics , Adenosine Deaminase/immunology , Adenosine Deaminase/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Base Sequence , Binding Sites/genetics , COVID-19/genetics , COVID-19/virology , Evolution, Molecular , Gene Expression/immunology , Humans , Immunity, Innate/genetics , Interferon-Induced Helicase, IFIH1/genetics , Interferon-Induced Helicase, IFIH1/immunology , Interferon-Induced Helicase, IFIH1/metabolism , Mutation , Protein Binding , RNA Editing/genetics , RNA-Binding Proteins/genetics , RNA-Binding Proteins/immunology , RNA-Binding Proteins/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Sequence Homology, Nucleic Acid , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
6.
Nucleic Acids Res ; 50(8): e47, 2022 05 06.
Article in English | MEDLINE | ID: covidwho-1684755

ABSTRACT

Gene-editing technologies, including the widespread usage of CRISPR endonucleases, have the potential for clinical treatments of various human diseases. Due to the rapid mutations of SARS-CoV-2, specific and effective prevention and treatment by CRISPR toolkits for coronavirus disease 2019 (COVID-19) are urgently needed to control the current pandemic spread. Here, we designed Type III CRISPR endonuclease antivirals for coronaviruses (TEAR-CoV) as a therapeutic to combat SARS-CoV-2 infection. We provided a proof of principle demonstration that TEAR-CoV-based RNA engineering approach leads to RNA-guided transcript degradation both in vitro and in eukaryotic cells, which could be used to broadly target RNA viruses. We report that TEAR-CoV not only cleaves SARS-CoV-2 genome and mRNA transcripts, but also degrades live influenza A virus (IAV), impeding viral replication in cells and in mice. Moreover, bioinformatics screening of gRNAs along RNA sequences reveals that a group of five gRNAs (hCoV-gRNAs) could potentially target 99.98% of human coronaviruses. TEAR-CoV also exerted specific targeting and cleavage of common human coronaviruses. The fast design and broad targeting of TEAR-CoV may represent a versatile antiviral approach for SARS-CoV-2 or potentially other emerging human coronaviruses.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antiviral Agents , COVID-19/therapy , Humans , Mice , Pandemics/prevention & control , RNA Editing/genetics , RNA, Guide/genetics , SARS-CoV-2/genetics
7.
Front Immunol ; 12: 690416, 2021.
Article in English | MEDLINE | ID: covidwho-1317226

ABSTRACT

The AID (activation-induced cytidine deaminase)/APOBEC (apolipoprotein B mRNA editing enzyme catalytic subunit) family with its multifaceted mode of action emerges as potent intrinsic host antiviral system that acts against a variety of DNA and RNA viruses including coronaviruses. All family members are cytosine-to-uracil deaminases that either have a profound role in driving a strong and specific humoral immune response (AID) or restricting the virus itself by a plethora of mechanisms (APOBECs). In this article, we highlight some of the key aspects apparently linking the AID/APOBECs and SARS-CoV-2. Among those is our discovery that APOBEC4 shows high expression in cell types and anatomical parts targeted by SARS-CoV-2. Additional focus is given by us to the lymphoid structures and AID as the master regulator of germinal center reactions, which result in antibody production by plasma and memory B cells. We propose the dissection of the AID/APOBECs gene signature towards decisive determinants of the patient-specific and/or the patient group-specific antiviral response. Finally, the patient-specific mapping of the AID/APOBEC polymorphisms should be considered in the light of COVID-19.


Subject(s)
APOBEC-1 Deaminase/genetics , COVID-19/enzymology , COVID-19/immunology , Cytidine Deaminase/genetics , SARS-CoV-2/genetics , Transcriptome , Antibodies, Viral/immunology , B-Lymphocytes/immunology , COVID-19/virology , Germinal Center/immunology , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Immunity, Humoral/genetics , Plasma Cells/immunology , Polymorphism, Genetic , RNA Editing/genetics , RNA, Viral/genetics
8.
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
10.
Sci Adv ; 6(25): eabb5813, 2020 06.
Article in English | MEDLINE | ID: covidwho-619103

ABSTRACT

The COVID-19 outbreak has become a global health risk, and understanding the response of the host to the SARS-CoV-2 virus will help to combat the disease. RNA editing by host deaminases is an innate restriction process to counter virus infection, but it is not yet known whether this process operates against coronaviruses. Here, we analyze RNA sequences from bronchoalveolar lavage fluids obtained from coronavirus-infected patients. We identify nucleotide changes that may be signatures of RNA editing: adenosine-to-inosine changes from ADAR deaminases and cytosine-to-uracil changes from APOBEC deaminases. Mutational analysis of genomes from different strains of Coronaviridae from human hosts reveals mutational patterns consistent with those observed in the transcriptomic data. However, the reduced ADAR signature in these data raises the possibility that ADARs might be more effective than APOBECs in restricting viral propagation. Our results thus suggest that both APOBECs and ADARs are involved in coronavirus genome editing, a process that may shape the fate of both virus and patient.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/metabolism , Coronavirus Infections/genetics , Host-Pathogen Interactions/genetics , Pneumonia, Viral/genetics , RNA Editing/genetics , Transcriptome , APOBEC Deaminases/genetics , APOBEC Deaminases/metabolism , Adenosine Deaminase/genetics , Adenosine Deaminase/metabolism , Base Sequence/genetics , Bronchoalveolar Lavage Fluid/virology , COVID-19 , Coronavirus Infections/virology , Genome, Viral/genetics , Humans , Mutation Rate , Nucleotides/genetics , Nucleotides/metabolism , Pandemics , Pneumonia, Viral/virology , RNA, Viral/genetics , SARS-CoV-2 , Virus Replication/genetics
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