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PeerJ 2022RNA viruses encoding a polymerase gene (riboviruses) dominate the known eukaryotic virome. High-throughput sequencing is revealing a wealth of new riboviruses known only...
RNA viruses encoding a polymerase gene (riboviruses) dominate the known eukaryotic virome. High-throughput sequencing is revealing a wealth of new riboviruses known only from sequence, precluding classification by traditional taxonomic methods. Sequence classification is often based on polymerase sequences, but standardised methods to support this approach are currently lacking. To address this need, we describe the polymerase palmprint, a segment of the palm sub-domain robustly delineated by well-conserved catalytic motifs. We present an algorithm, Palmscan, which identifies palmprints in nucleotide and amino acid sequences; PALMdb, a collection of palmprints derived from public sequence databases; and palmID, a public website implementing palmprint identification, search, and annotation. Together, these methods demonstrate a proof-of-concept workflow for high-throughput characterisation of RNA viruses, paving the path for the continued rapid growth in RNA virus discovery anticipated in the coming decade.
Topics: RNA Viruses; Amino Acid Sequence; Eukaryota; Nucleotidyltransferases; Algorithms
PubMed: 36258794
DOI: 10.7717/peerj.14055 -
Physiological Genomics Nov 2013RNA viruses represent the predominant cause of many clinically relevant viral diseases in humans. Among several evolutionary advantages acquired by RNA viruses, the... (Review)
Review
RNA viruses represent the predominant cause of many clinically relevant viral diseases in humans. Among several evolutionary advantages acquired by RNA viruses, the ability to usurp host cellular machinery and evade antiviral immune responses is imperative. During the past decade, RNA interference mechanisms, especially microRNA (miRNA)-mediated regulation of cellular protein expression, have revolutionized our understanding of host-viral interactions. Although it is well established that several DNA viruses express miRNAs that play crucial roles in their pathogenesis, expression of miRNAs by RNA viruses remains controversial. However, modulation of the miRNA machinery by RNA viruses may confer multiple benefits for enhanced viral replication and survival in host cells. In this review, we discuss the current literature on RNA viruses that may encode miRNAs and the varied advantages of engineering RNA viruses to express miRNAs as potential vectors for gene therapy. In addition, we review how different families of RNA viruses can alter miRNA machinery for productive replication, evasion of antiviral immune responses, and prolonged survival. We underscore the need to further explore the complex interactions of RNA viruses with host miRNAs to augment our understanding of host-virus interplay.
Topics: Animals; Genetic Therapy; Genetic Vectors; Host-Pathogen Interactions; Humans; MicroRNAs; RNA Interference; RNA Virus Infections; RNA Viruses; RNA, Viral
PubMed: 24046280
DOI: 10.1152/physiolgenomics.00112.2013 -
Scientific Reports Mar 2021The replication machinery of most RNA viruses lacks proofreading mechanisms. As a result, RNA virus populations harbor a large amount of genetic diversity that confers...
The replication machinery of most RNA viruses lacks proofreading mechanisms. As a result, RNA virus populations harbor a large amount of genetic diversity that confers them the ability to rapidly adapt to changes in their environment. In this work, we investigate whether further increasing the initial population diversity of a model RNA virus can improve adaptation to a single selection pressure, thermal inactivation. For this, we experimentally increased the diversity of coxsackievirus B3 (CVB3) populations across the capsid region. We then compared the ability of these high diversity CVB3 populations to achieve resistance to thermal inactivation relative to standard CVB3 populations in an experimental evolution setting. We find that viral populations with high diversity are better able to achieve resistance to thermal inactivation at both the temperature employed during experimental evolution as well as at a more extreme temperature. Moreover, we identify mutations in the CVB3 capsid that confer resistance to thermal inactivation, finding significant mutational epistasis. Our results indicate that even naturally diverse RNA virus populations can benefit from experimental augmentation of population diversity for optimal adaptation and support the use of such viral populations in directed evolution efforts that aim to select viruses with desired characteristics.
Topics: Amino Acid Substitution; Biodiversity; Biological Evolution; Capsid; Capsid Proteins; Cell Line; Computational Biology; Genetic Variation; Humans; Mutation; RNA Viruses
PubMed: 33767337
DOI: 10.1038/s41598-021-86375-z -
Antiviral Research Apr 2008RNA viruses are a significant source of morbidity and mortality in humans every year. Additionally, the potential use of these viruses in acts of bioterrorism poses a... (Review)
Review
RNA viruses are a significant source of morbidity and mortality in humans every year. Additionally, the potential use of these viruses in acts of bioterrorism poses a threat to national security. Given the paucity of vaccines or postexposure therapeutics for many highly pathogenic RNA viruses, novel treatments are badly needed. Sequence-based drug design, under development for almost 20 years, is proving effective in animal models and has moved into clinical trials. Important advances in the field include the characterization of RNA interference in mammalian cells and chemical modifications that can dramatically increase the in vivo stability of therapeutic oligonucleotides. Antisense strategies utilize single-stranded DNA oligonucleotides that inhibit protein production by mediating the catalytic degradation of target mRNA, or by binding to sites on mRNA essential for translation. Double-stranded RNA oligonucleotides, known as short-interfering RNAs (siRNAs), also mediate the catalytic degradation of complementary mRNAs. As RNA virus infection is predicated on the delivery, replication, and translation of viral RNA, these pathogens present an obvious target for the rapidly advancing field of sequence-specific therapeutics. Antisense oligonucleotides or siRNAs can be designed to target the viral RNA genome or viral transcripts. This article reviews current knowledge on therapeutic applications of antisense and RNA interference for highly pathogenic RNA viral infections.
Topics: Animals; Cell Line; Disease Models, Animal; Guinea Pigs; Humans; Mice; Morpholines; Morpholinos; Oligonucleotides, Antisense; RNA Interference; RNA Virus Infections; RNA Viruses; RNA, Small Interfering; RNA, Viral
PubMed: 18258313
DOI: 10.1016/j.antiviral.2007.12.008 -
Virology Jun 2017The complete nucleotide sequence of a new RNA mycovirus in the KY isolate of Phomopsis longicolla Hobbs 1985 and its protoplasts subcultures p5, p9, and ME711 was...
The complete nucleotide sequence of a new RNA mycovirus in the KY isolate of Phomopsis longicolla Hobbs 1985 and its protoplasts subcultures p5, p9, and ME711 was discovered. The virus, provisionally named Phomopsis longicolla RNA virus 1 (PlRV1), was localized in mitochondria and was determined to have a genome 2822 nucleotides long. A single open reading frame could be translated in silico by both standard and mitochondrial genetic codes into a product featuring conservative domains for an RNA-dependent RNA polymerase (RdRp). The RdRp of PlRV1 has no counterpart among mycoviruses, but it is about 30% identical with the RdRp of plant ourmiaviruses. Recently, new mycoviruses related to plant ourmiaviruses and forming one clade with PlRV1 have been discovered. This separate clade could represent the crucial link between plant and fungal viruses.
Topics: Amino Acid Sequence; Ascomycota; Base Sequence; Fungal Viruses; Genome, Viral; Molecular Sequence Data; Open Reading Frames; Phylogeny; Plant Diseases; Plant Viruses; RNA Viruses; RNA, Viral; Viral Proteins
PubMed: 28288321
DOI: 10.1016/j.virol.2017.03.003 -
Virus Research Jan 2018Virus metagenomics is a young research filed but it has already transformed our understanding of virus diversity and evolution, and illuminated at a new level the... (Review)
Review
Virus metagenomics is a young research filed but it has already transformed our understanding of virus diversity and evolution, and illuminated at a new level the connections between virus evolution and the evolution and ecology of the hosts. In this review article, we examine the new picture of the evolution of RNA viruses, the dominant component of the eukaryotic virome, that is emerging from metagenomic data analysis. The major expansion of many groups of RNA viruses through metagenomics allowed the construction of substantially improved phylogenetic trees for the conserved virus genes, primarily, the RNA-dependent RNA polymerases (RdRp). In particular, a new superfamily of widespread, small positive-strand RNA viruses was delineated that unites tombus-like and noda-like viruses. Comparison of the genome architectures of RNA viruses discovered by metagenomics and by traditional methods reveals an extent of gene module shuffling among diverse virus genomes that far exceeds the previous appreciation of this evolutionary phenomenon. Most dramatically, inclusion of the metagenomic data in phylogenetic analyses of the RdRp resulted in the identification of numerous, strongly supported groups that encompass RNA viruses from diverse hosts including different groups of protists, animals and plants. Notwithstanding potential caveats, in particular, incomplete and uneven sampling of eukaryotic taxa, these highly unexpected findings reveal horizontal virus transfer (HVT) between diverse hosts as the central aspect of RNA virus evolution. The vast and diverse virome of invertebrates, particularly nematodes and arthropods, appears to be the reservoir, from which the viromes of plants and vertebrates evolved via multiple HVT events.
Topics: Animals; Arthropods; Disease Transmission, Infectious; Evolution, Molecular; Gene Expression; Genetic Variation; Genome, Viral; Metagenomics; Nematoda; Phylogeny; Plants; Prokaryotic Cells; RNA Viruses; RNA-Dependent RNA Polymerase; Vertebrates; Viral Proteins
PubMed: 29103997
DOI: 10.1016/j.virusres.2017.10.020 -
Philosophical Transactions of the Royal... Aug 2016In their search to understand the evolution of biological complexity, John Maynard Smith and Eörs Szathmáry put forward the notion of major evolutionary transitions as... (Review)
Review
In their search to understand the evolution of biological complexity, John Maynard Smith and Eörs Szathmáry put forward the notion of major evolutionary transitions as those in which elementary units get together to generate something new, larger and more complex. The origins of chromosomes, eukaryotic cells, multicellular organisms, colonies and, more recently, language and technological societies are examples that clearly illustrate this notion. However, a transition may be considered as anecdotal or as major depending on the specific level of biological organization under study. In this contribution, I will argue that transitions may also be occurring at a much smaller scale of biological organization: the viral world. Not only that, but also that we can observe in real time how these major transitions take place during experimental evolution. I will review the outcome of recent evolution experiments with viruses that illustrate four major evolutionary transitions: (i) the origin of a new virus that infects an otherwise inaccessible host and completely changes the way it interacts with the host regulatory and metabolic networks, (ii) the incorporation and loss of genes, (iii) the origin of segmented genomes from a non-segmented one, and (iv) the evolution of cooperative behaviour and cheating between different viruses or strains during co-infection of the same host.This article is part of the themed issue 'The major synthetic evolutionary transitions'.
Topics: Biological Evolution; Coinfection; Evolution, Molecular; Genome, Viral; Microbial Interactions; RNA Viruses
PubMed: 27431519
DOI: 10.1098/rstb.2015.0441 -
Antiviral Chemistry & Chemotherapy 2018Influenza virus, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, coronaviruses, and rhinoviruses are among the most common viruses causing mild... (Review)
Review
Influenza virus, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, coronaviruses, and rhinoviruses are among the most common viruses causing mild seasonal colds. These RNA viruses can also cause lower respiratory tract infections leading to bronchiolitis and pneumonia. Young children, the elderly, and patients with compromised cardiac, pulmonary, or immune systems are at greatest risk for serious disease associated with these RNA virus respiratory infections. In addition, swine and avian influenza viruses, together with severe acute respiratory syndrome-associated and Middle Eastern respiratory syndrome coronaviruses, represent significant pandemic threats to the general population. In this review, we describe the current medical need resulting from respiratory infections caused by RNA viruses, which justifies drug discovery efforts to identify new therapeutic agents. The RNA polymerase of respiratory viruses represents an attractive target for nucleoside and nucleotide analogs acting as inhibitors of RNA chain synthesis. Here, we present the molecular, biochemical, and structural fundamentals of the polymerase of the four major families of RNA respiratory viruses: Orthomyxoviridae, Pneumoviridae/Paramyxoviridae, Coronaviridae, and Picornaviridae. We summarize past and current efforts to develop nucleoside and nucleotide analogs as antiviral agents against respiratory virus infections. This includes molecules with very broad antiviral spectrum such as ribavirin and T-705 (favipiravir), and others targeting more specifically one or a few virus families. Recent advances in our understanding of the structure(s) and function(s) of respiratory virus polymerases will likely support the discovery and development of novel nucleoside analogs.
Topics: Antiviral Agents; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Nucleosides; RNA Virus Infections; RNA Viruses; Respiratory Tract Infections
PubMed: 29562753
DOI: 10.1177/2040206618764483 -
Science (New York, N.Y.) Jul 2021In mammals, early resistance to viruses relies on interferons, which protect differentiated cells but not stem cells from viral replication. Many other organisms rely...
In mammals, early resistance to viruses relies on interferons, which protect differentiated cells but not stem cells from viral replication. Many other organisms rely instead on RNA interference (RNAi) mediated by a specialized Dicer protein that cleaves viral double-stranded RNA. Whether RNAi also contributes to mammalian antiviral immunity remains controversial. We identified an isoform of Dicer, named antiviral Dicer (aviD), that protects tissue stem cells from RNA viruses-including Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-by dicing viral double-stranded RNA to orchestrate antiviral RNAi. Our work sheds light on the molecular regulation of antiviral RNAi in mammalian innate immunity, in which different cell-intrinsic antiviral pathways can be tailored to the differentiation status of cells.
Topics: Alternative Splicing; Animals; Brain; Cell Line; DEAD-box RNA Helicases; Humans; Immunity, Innate; Isoenzymes; Mice; Organoids; RNA Interference; RNA Virus Infections; RNA Viruses; RNA, Double-Stranded; RNA, Small Interfering; RNA, Viral; Ribonuclease III; SARS-CoV-2; Stem Cells; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 34244417
DOI: 10.1126/science.abg2264 -
Journal of Virology Sep 2021The emergence of the CRISPR/Cas system as a technology has transformed our ability to modify nucleic acids, and the CRISPR/Cas13 system has been used to target RNA....
The emergence of the CRISPR/Cas system as a technology has transformed our ability to modify nucleic acids, and the CRISPR/Cas13 system has been used to target RNA. CasRx is a small type VI-D effector (Cas13d) with RNA knockdown efficiency that may have an interference effect on RNA viruses. However, the RNA virus-targeting activity of CasRx still needs to be verified in vertebrates. In this study, we successfully engineered a highly effective CasRx system for fish virus interference. We designed synthetic mRNA coding for CasRx and used CRISPR RNAs to guide it to target the red-spotted grouper nervous necrosis virus (RGNNV). This technique resulted in significant interference with virus infections both and . These results indicate that CRISPR/CasRx can be used to engineer interference against RNA viruses in fish, which provides a potential novel mechanism for RNA-guided immunity against other RNA viruses in vertebrates. RNA viruses are important viral pathogens infecting vertebrates and mammals. RNA virus populations are highly dynamic due to short generation times, large population sizes, and high mutation frequencies. Therefore, it is difficult to find widely effective ways to inhibit RNA viruses, and we urgently need to develop effective antiviral methods. CasRx is a small type VI-D effector (Cas13d) with RNA knockdown efficiency that can have an interference effect on RNA viruses. Nervous necrosis virus (NNV), a nonenveloped positive-strand RNA virus, is one of the most serious viral pathogens, infecting more than 40 cultured fish species and resulting in huge economic losses worldwide. Here, we establish a novel effective CasRx system for RNA virus interference using NNV and grouper (Epinephelus coioides) as a model. Our data showed that CasRx was most robust for RNA virus interference applications in fish, and we demonstrate its suitability for studying key questions related to virus biology.
Topics: Animals; CRISPR-Associated Proteins; CRISPR-Cas Systems; Fish Diseases; Nodaviridae; Perciformes; RNA Interference; RNA Virus Infections; RNA, Viral
PubMed: 34287045
DOI: 10.1128/JVI.00461-21