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1.
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
2.
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
3.
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
5.
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
6.
Proc Natl Acad Sci U S A ; 119(6)2022 02 08.
Article in English | MEDLINE | ID: covidwho-1642083

ABSTRACT

Adenosine deaminases acting on RNA (ADAR) are RNA-editing enzymes that may restrict viral infection. We have utilized deep sequencing to determine adenosine to guanine (A→G) mutations, signifying ADAR activity, in clinical samples retrieved from 93 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients in the early phase of the COVID-19 pandemic. A→G mutations were detected in 0.035% (median) of RNA residues and were predominantly nonsynonymous. These mutations were rarely detected in the major viral population but were abundant in minor viral populations in which A→G was more prevalent than any other mutation (P < 0.001). The A→G substitutions accumulated in the spike protein gene at positions corresponding to amino acids 505 to 510 in the receptor binding motif and at amino acids 650 to 655. The frequency of A→G mutations in minor viral populations was significantly associated with low viral load (P < 0.001). We additionally analyzed A→G mutations in 288,247 SARS-CoV-2 major (consensus) sequences representing the dominant viral population. The A→G mutations observed in minor viral populations in the initial patient cohort were increasingly detected in European consensus sequences between March and June 2020 (P < 0.001) followed by a decline of these mutations in autumn and early winter (P < 0.001). We propose that ADAR-induced deamination of RNA is a significant source of mutated SARS-CoV-2 and hypothesize that the degree of RNA deamination may determine or reflect viral fitness and infectivity.


Subject(s)
Adenosine Deaminase/genetics , COVID-19/epidemiology , Point Mutation , RNA Editing , RNA, Viral/genetics , RNA-Binding Proteins/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Adenosine/metabolism , Adenosine Deaminase/metabolism , Adult , Aged , Aged, 80 and over , Amino Acid Substitution , COVID-19/genetics , COVID-19/transmission , COVID-19/virology , Deamination , Female , Genetic Fitness , Genome, Viral , Guanine/metabolism , Host-Pathogen Interactions/genetics , Humans , Male , Middle Aged , RNA, Viral/metabolism , RNA-Binding Proteins/metabolism , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity , Signal Transduction , Spike Glycoprotein, Coronavirus/metabolism , Sweden/epidemiology , Viral Load , Virulence
7.
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
8.
Genome Biol Evol ; 13(11)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1483441

ABSTRACT

Adenosine Deaminases that Act on RNA (ADARs) are RNA editing enzymes that play a dynamic and nuanced role in regulating transcriptome and proteome diversity. This editing can be highly selective, affecting a specific site within a transcript, or nonselective, resulting in hyperediting. ADAR editing is important for regulating neural functions and autoimmunity, and has a key role in the innate immune response to viral infections, where editing can have a range of pro- or antiviral effects and can contribute to viral evolution. Here we examine the role of ADAR editing across a broad range of viral groups. We propose that the effect of ADAR editing on viral replication, whether pro- or antiviral, is better viewed as an axis rather than a binary, and that the specific position of a given virus on this axis is highly dependent on virus- and host-specific factors, and can change over the course of infection. However, more research needs to be devoted to understanding these dynamic factors and how they affect virus-ADAR interactions and viral evolution. Another area that warrants significant attention is the effect of virus-ADAR interactions on host-ADAR interactions, particularly in light of the crucial role of ADAR in regulating neural functions. Answering these questions will be essential to developing our understanding of the relationship between ADAR editing and viral infection. In turn, this will further our understanding of the effects of viruses such as SARS-CoV-2, as well as many others, and thereby influence our approach to treating these deadly diseases.


Subject(s)
Adenosine Deaminase/metabolism , RNA Editing , RNA Viruses/genetics , Adenosine Deaminase/genetics , Animals , Evolution, Molecular , Host-Pathogen Interactions/immunology , Humans , Immunity , RNA Viruses/classification , RNA Viruses/physiology , RNA, Viral/genetics , RNA, Viral/metabolism , Virus Replication/genetics
10.
Viruses ; 13(7)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1335222

ABSTRACT

Viral infections cause a variety of acute and chronic human diseases, sometimes resulting in small local outbreaks, or in some cases spreading across the globe and leading to global pandemics. Understanding and exploiting virus-host interactions is instrumental for identifying host factors involved in viral replication, developing effective antiviral agents, and mitigating the severity of virus-borne infectious diseases. The diversity of CRISPR systems and CRISPR-based tools enables the specific modulation of innate immune responses and has contributed impressively to the fields of virology and immunology in a very short time. In this review, we describe the most recent advances in the use of CRISPR systems for basic and translational studies of virus-host interactions.


Subject(s)
Antiviral Agents/immunology , Antiviral Agents/pharmacology , CRISPR-Cas Systems , Virus Diseases/immunology , Animals , Exoribonucleases/metabolism , Host Microbial Interactions/immunology , Humans , Immune Evasion , Immunity, Innate , Interferons/genetics , Interferons/immunology , RNA Editing , Transcriptome , Virus Diseases/virology , Virus Internalization , Virus Replication/drug effects
11.
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
12.
Cells ; 10(6)2021 06 20.
Article in English | MEDLINE | ID: covidwho-1273395

ABSTRACT

The current SARS-CoV-2 pandemic underscores the importance of understanding the evolution of RNA genomes. While RNA is subject to the formation of similar lesions as DNA, the evolutionary and physiological impacts RNA lesions have on viral genomes are yet to be characterized. Lesions that may drive the evolution of RNA genomes can induce breaks that are repaired by recombination or can cause base substitution mutagenesis, also known as base editing. Over the past decade or so, base editing mutagenesis of DNA genomes has been subject to many studies, revealing that exposure of ssDNA is subject to hypermutation that is involved in the etiology of cancer. However, base editing of RNA genomes has not been studied to the same extent. Recently hypermutation of single-stranded RNA viral genomes have also been documented though its role in evolution and population dynamics. Here, we will summarize the current knowledge of key mechanisms and causes of RNA genome instability covering areas from the RNA world theory to the SARS-CoV-2 pandemic of today. We will also highlight the key questions that remain as it pertains to RNA genome instability, mutations accumulation, and experimental strategies for addressing these questions.


Subject(s)
Evolution, Molecular , RNA, Viral/genetics , SARS-CoV-2/genetics , COVID-19/epidemiology , COVID-19/virology , Genome, Viral/genetics , Humans , Mutation , Pandemics , RNA Editing/physiology , RNA Stability/physiology
13.
PLoS Pathog ; 17(6): e1009596, 2021 06.
Article in English | MEDLINE | ID: covidwho-1249581

ABSTRACT

The rapid evolution of RNA viruses has been long considered to result from a combination of high copying error frequencies during RNA replication, short generation times and the consequent extensive fixation of neutral or adaptive changes over short periods. While both the identities and sites of mutations are typically modelled as being random, recent investigations of sequence diversity of SARS coronavirus 2 (SARS-CoV-2) have identified a preponderance of C->U transitions, proposed to be driven by an APOBEC-like RNA editing process. The current study investigated whether this phenomenon could be observed in datasets of other RNA viruses. Using a 5% divergence filter to infer directionality, 18 from 36 datasets of aligned coding region sequences from a diverse range of mammalian RNA viruses (including Picornaviridae, Flaviviridae, Matonaviridae, Caliciviridae and Coronaviridae) showed a >2-fold base composition normalised excess of C->U transitions compared to U->C (range 2.1x-7.5x), with a consistently observed favoured 5' U upstream context. The presence of genome scale RNA secondary structure (GORS) was the only other genomic or structural parameter significantly associated with C->U/U->C transition asymmetries by multivariable analysis (ANOVA), potentially reflecting RNA structure dependence of sites targeted for C->U mutations. Using the association index metric, C->U changes were specifically over-represented at phylogenetically uninformative sites, potentially paralleling extensive homoplasy of this transition reported in SARS-CoV-2. Although mechanisms remain to be functionally characterised, excess C->U substitutions accounted for 11-14% of standing sequence variability of structured viruses and may therefore represent a potent driver of their sequence diversification and longer-term evolution.


Subject(s)
Mammals/virology , Mutation , RNA Viruses/genetics , SARS-CoV-2/genetics , APOBEC Deaminases/metabolism , Animals , Base Sequence , COVID-19/virology , Cytidine/genetics , DNA Damage/physiology , Evolution, Molecular , Gene Expression Regulation, Viral , Genome, Viral , Host-Pathogen Interactions/genetics , Humans , Nucleic Acid Conformation , Phylogeny , RNA Editing/physiology , RNA Viruses/classification , RNA, Viral/chemistry , RNA, Viral/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/classification , Sequence Analysis, RNA , Transcription, Genetic/genetics , Uridine/genetics
14.
Nat Methods ; 18(5): 499-506, 2021 05.
Article in English | MEDLINE | ID: covidwho-1220210

ABSTRACT

Competitive coevolution between microbes and viruses has led to the diversification of CRISPR-Cas defense systems against infectious agents. By analyzing metagenomic terabase datasets, we identified two compact families (775 to 803 amino acids (aa)) of CRISPR-Cas ribonucleases from hypersaline samples, named Cas13X and Cas13Y. We engineered Cas13X.1 (775 aa) for RNA interference experiments in mammalian cell lines. We found Cas13X.1 could tolerate single-nucleotide mismatches in RNA recognition, facilitating prophylactic RNA virus inhibition. Moreover, a minimal RNA base editor, composed of engineered deaminase (385 aa) and truncated Cas13X.1 (445 aa), exhibited robust editing efficiency and high specificity to induce RNA base conversions. Our results suggest that there exist untapped bacterial defense systems in natural microbes that can function efficiently in mammalian cells, and thus potentially are useful for RNA-editing-based research.


Subject(s)
CRISPR-Cas Systems , RNA Editing , RNA, Bacterial , Animals , Bacterial Proteins , Cell Line , Cloning, Molecular , Databases, Nucleic Acid , Dogs , Humans , Mice , RNA Interference
15.
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
16.
Clin Immunol ; 226: 108699, 2021 05.
Article in English | MEDLINE | ID: covidwho-1101151

ABSTRACT

RNA editing is a fundamental biological process with 2 major forms, namely adenosine-to-inosine (A-to-I, recognized as A-to-G) and cytosine-to-uracil (C-to-U) deamination, mediated by ADAR and APOBEC enzyme families, respectively. A-to-I RNA editing has been shown to directly affect the genome/transcriptome of RNA viruses with significant repercussions for viral protein synthesis, proliferation and infectivity, while it also affects recognition of double-stranded RNAs by cytosolic receptors controlling the host innate immune response. Recent evidence suggests that RNA editing may be present in SARS-CoV-2 genome/transcriptome. The majority of mapped mutations in SARS-CoV-2 genome are A-to-G/U-to-C(opposite strand) and C-to-U/G-to-A(opposite strand) substitutions comprising potential ADAR-/APOBEC-mediated deamination events. A single nucleotide substitution can have dramatic effects on SARS-CoV-2 infectivity as shown by the D614G(A-to-G) substitution in the spike protein. Future studies utilizing serial sampling from patients with COVID-19 are warranted to delineate whether RNA editing affects viral replication and/or the host immune response to SARS-CoV-2.


Subject(s)
APOBEC Deaminases/metabolism , Adenosine Deaminase/metabolism , COVID-19/immunology , Immunity, Innate , RNA Editing , RNA Viruses/genetics , RNA-Binding Proteins/metabolism , SARS-CoV-2/genetics , APOBEC Deaminases/genetics , Adenosine Deaminase/genetics , COVID-19/enzymology , COVID-19/virology , Humans , Mutation , RNA Viruses/pathogenicity , RNA, Double-Stranded/metabolism , RNA-Binding Proteins/genetics , SARS-CoV-2/metabolism
17.
Virology ; 556: 62-72, 2021 04.
Article in English | MEDLINE | ID: covidwho-1065649

ABSTRACT

Members of the APOBEC family of cytidine deaminases show antiviral activities in mammalian cells through lethal editing in the genomes of small DNA viruses, herpesviruses and retroviruses, and potentially those of RNA viruses such as coronaviruses. Consistent with the latter, APOBEC-like directional C→U transitions of genomic plus-strand RNA are greatly overrepresented in SARS-CoV-2 genome sequences of variants emerging during the COVID-19 pandemic. A C→U mutational process may leave evolutionary imprints on coronavirus genomes, including extensive homoplasy from editing and reversion at targeted sites and the occurrence of driven amino acid sequence changes in viral proteins. If sustained over longer periods, this process may account for the previously reported marked global depletion of C and excess of U bases in human seasonal coronavirus genomes. This review synthesizes the current knowledge on APOBEC evolution and function and the evidence of their role in APOBEC-mediated genome editing of SARS-CoV-2 and other coronaviruses.


Subject(s)
APOBEC Deaminases/metabolism , Coronavirus/genetics , Evolution, Molecular , Genome, Viral/genetics , RNA Editing , APOBEC Deaminases/chemistry , APOBEC Deaminases/genetics , Animals , Coronavirus Infections/virology , Humans , Mutation , SARS-CoV-2/genetics
19.
Virologie (Montrouge) ; 24(6): 381-418, 2020 12 01.
Article in French | MEDLINE | ID: covidwho-1030336

ABSTRACT

The innate immune response is nonspecific and constitutes the first line of defense against infections by pathogens, mainly by enabling their elimination by phagocytosis or apoptosis. In immune cells, this response is characterized, amongst others, by the synthesis of restriction factors, a class of proteins whose role is to inhibit viral replication. Among them, the proteins of the APOBEC3 (Apolipoprotein B mRNA-editing Enzyme Catalytic polypeptide-like 3 or A3) family are major antiviral factors that target a wide range of viruses. One of their targets is the Human Immunodeficiency Virus Type 1 (HIV-1): the deaminase activity of some A3 proteins converts a fraction of cytidines of the viral genome into uridines, impairing its expression. Nevertheless, HIV-1 counteracts A3 proteins thanks to its Vif protein, which inhibits them by hijacking several cellular mechanisms. Besides, APOBEC3 proteins help maintaining the genome integrity by inhibiting retroelements but they also contribute to carcinogenesis, as it is the case for A3A and A3B, two major factors in this process. The large range of A3 activities, combined with recent studies showing their implication in the regulation of emerging viruses (Zika, SARS-CoV-2), allow A3 and their viral partners to be considered as therapeutic areas.


Subject(s)
APOBEC Deaminases/physiology , COVID-19/immunology , Immunity, Innate , Adult , Amino Acid Motifs , Animals , Cell Cycle Proteins/metabolism , Cytidine Deaminase/physiology , DNA Repair , DNA, Viral/metabolism , Deamination , Humans , Mammals/metabolism , MicroRNAs/genetics , Models, Molecular , Molecular Targeted Therapy , Mutagenesis , Neoplasms/enzymology , Neoplasms/etiology , Neoplasms/genetics , Prognosis , Protein Conformation , RNA Editing , Structure-Activity Relationship , Transcription, Genetic , Viral Proteins/metabolism , Virus Diseases/drug therapy , Virus Diseases/enzymology , Virus Diseases/immunology , Virus Replication
20.
Nat Commun ; 11(1): 5986, 2020 11 25.
Article in English | MEDLINE | ID: covidwho-947534

ABSTRACT

COVID-19 is caused by the coronavirus SARS-CoV-2, which jumped into the human population in late 2019 from a currently uncharacterised animal reservoir. Due to this recent association with humans, SARS-CoV-2 may not yet be fully adapted to its human host. This has led to speculations that SARS-CoV-2 may be evolving towards higher transmissibility. The most plausible mutations under putative natural selection are those which have emerged repeatedly and independently (homoplasies). Here, we formally test whether any homoplasies observed in SARS-CoV-2 to date are significantly associated with increased viral transmission. To do so, we develop a phylogenetic index to quantify the relative number of descendants in sister clades with and without a specific allele. We apply this index to a curated set of recurrent mutations identified within a dataset of 46,723 SARS-CoV-2 genomes isolated from patients worldwide. We do not identify a single recurrent mutation in this set convincingly associated with increased viral transmission. Instead, recurrent mutations currently in circulation appear to be evolutionary neutral and primarily induced by the human immune system via RNA editing, rather than being signatures of adaptation. At this stage we find no evidence for significantly more transmissible lineages of SARS-CoV-2 due to recurrent mutations.


Subject(s)
COVID-19/transmission , Genetic Fitness , Host-Pathogen Interactions/genetics , Mutation Rate , SARS-CoV-2/genetics , Alleles , Animals , COVID-19/epidemiology , COVID-19/virology , Genome, Viral/genetics , Humans , Pandemics , Phylogeny , RNA Editing , RNA, Viral/genetics , SARS-CoV-2/pathogenicity , Species Specificity
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