Inhibitions of Positive-Sense (ss) RNA Viruses RNA-Dependent RNA Polymerases

2009 ◽  
Vol 5 (4) ◽  
pp. 234-244 ◽  
Author(s):  
Kajohn Boonrod ◽  
Gabriele Krczal
2016 ◽  
Vol 90 (16) ◽  
pp. 7415-7428 ◽  
Author(s):  
Nicole R. Sexton ◽  
Everett Clinton Smith ◽  
Hervé Blanc ◽  
Marco Vignuzzi ◽  
Olve B. Peersen ◽  
...  

ABSTRACTPositive-sense RNA viruses encode RNA-dependent RNA polymerases (RdRps) essential for genomic replication. With the exception of the large nidoviruses, such as coronaviruses (CoVs), RNA viruses lack proofreading and thus are dependent on RdRps to control nucleotide selectivity and fidelity. CoVs encode a proofreading exonuclease in nonstructural protein 14 (nsp14-ExoN), which confers a greater-than-10-fold increase in fidelity compared to other RNA viruses. It is unknown to what extent the CoV polymerase (nsp12-RdRp) participates in replication fidelity. We sought to determine whether homology modeling could identify putative determinants of nucleotide selectivity and fidelity in CoV RdRps. We modeled the CoV murine hepatitis virus (MHV) nsp12-RdRp structure and superimposed it on solved picornaviral RdRp structures. Fidelity-altering mutations previously identified in coxsackie virus B3 (CVB3) were mapped onto the nsp12-RdRp model structure and then engineered into the MHV genome with [nsp14-ExoN(+)] or without [nsp14-ExoN(−)] ExoN activity. Using this method, we identified two mutations conferring resistance to the mutagen 5-fluorouracil (5-FU): nsp12-M611F and nsp12-V553I. For nsp12-V553I, we also demonstrate resistance to the mutagen 5-azacytidine (5-AZC) and decreased accumulation of mutations. Resistance to 5-FU, and a decreased number of genomic mutations, was effectively masked by nsp14-ExoN proofreading activity. These results indicate that nsp12-RdRp likely functions in fidelity regulation and that, despite low sequence conservation, some determinants of RdRp nucleotide selectivity are conserved across RNA viruses. The results also indicate that, with regard to nucleotide selectivity, nsp14-ExoN is epistatic to nsp12-RdRp, consistent with its proposed role in a multiprotein replicase-proofreading complex.IMPORTANCERNA viruses have evolutionarily fine-tuned replication fidelity to balance requirements for genetic stability and diversity. Responsibility for replication fidelity in RNA viruses has been attributed to the RNA-dependent RNA polymerases, with mutations in RdRps for multiple RNA viruses shown to alter fidelity and attenuate virus replication and virulence. Coronaviruses (CoVs) are the only known RNA viruses to encode a proofreading exonuclease (nsp14-ExoN), as well as other replicase proteins involved in regulation of fidelity. This report shows that the CoV RdRp (nsp12) likely functions in replication fidelity; that residue determinants of CoV RdRp nucleotide selectivity map to similar structural regions of other, unrelated RNA viral polymerases; and that for CoVs, the proofreading activity of the nsp14-ExoN is epistatic to the function of the RdRp in fidelity.


Author(s):  
Farzaneh Shobeirian

Background: Coronaviruses are non-segmented enveloped positive-sense single-strand RNA viruses, and COVID-19 is the seventh known coronavirus, infecting humans. Objective: As the COVID-19 continued to spread the world wildly, every radiologist or clinician needs to be familiar with its imaging findings. Methods: In this study, we reviewed available studies to provide a comprehensive statement on COVID-19 imaging findings. Results: Ground-glass opacities, linear opacities, interlobular septal thickening, consolidation, and Crazy-paving patterns are the most frequent findings in computed tomography (CT) of lungs in patients with COVID-19 pneumonia, which are mostly bilateral, multifocal, and peripheral. Staff needs to follow some rules to reduce infection transmission. Conclusion: COVID-19 pneumonia is a new global concern which has many unknown features. In this article, the radiologic characteristics of COVID-19 pneumonia are discussed. We also discussed appropriate protective measures that the radiology team should be aware of.


Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 979
Author(s):  
Tongtong Zhu ◽  
Ana Fernandez-Sesma

Flaviviruses are arthropod-borne RNA viruses that have been used extensively to study host antiviral responses. Often selected just to represent standard single-stranded positive-sense RNA viruses in early studies, the Flavivirus genus over time has taught us how truly unique it is in its remarkable ability to target not just the RNA sensory pathways but also the cytosolic DNA sensing system for its successful replication inside the host cell. This review summarizes the main developments on the unexpected antagonistic strategies utilized by different flaviviruses, with RNA genomes, against the host cyclic GAMP synthase (cGAS)/stimulator of interferon genes (STING) cytosolic DNA sensing pathway in mammalian systems. On the basis of the recent advancements on this topic, we hypothesize that the mechanisms of viral sensing and innate immunity are much more fluid than what we had anticipated, and both viral and host factors will continue to be found as important factors contributing to the host innate immune system in the future.


Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 685 ◽  
Author(s):  
Cormac McCarthy ◽  
Nadishka Jayawardena ◽  
Laura N. Burga ◽  
Mihnea Bostina

Oncolytic viruses (OVs) form a group of novel anticancer therapeutic agents which selectively infect and lyse cancer cells. Members of several viral families, including Picornaviridae, have been shown to have anticancer activity. Picornaviruses are small icosahedral non-enveloped, positive-sense, single-stranded RNA viruses infecting a wide range of hosts. They possess several advantages for development for cancer therapy: Their genomes do not integrate into host chromosomes, do not encode oncogenes, and are easily manipulated as cDNA. This review focuses on the picornaviruses investigated for anticancer potential and the mechanisms that underpin this specificity.


mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Yuri I. Wolf ◽  
Darius Kazlauskas ◽  
Jaime Iranzo ◽  
Adriana Lucía-Sanz ◽  
Jens H. Kuhn ◽  
...  

ABSTRACTViruses with RNA genomes dominate the eukaryotic virome, reaching enormous diversity in animals and plants. The recent advances of metaviromics prompted us to perform a detailed phylogenomic reconstruction of the evolution of the dramatically expanded global RNA virome. The only universal gene among RNA viruses is the gene encoding the RNA-dependent RNA polymerase (RdRp). We developed an iterative computational procedure that alternates the RdRp phylogenetic tree construction with refinement of the underlying multiple-sequence alignments. The resulting tree encompasses 4,617 RNA virus RdRps and consists of 5 major branches; 2 of the branches include positive-sense RNA viruses, 1 is a mix of positive-sense (+) RNA and double-stranded RNA (dsRNA) viruses, and 2 consist of dsRNA and negative-sense (−) RNA viruses, respectively. This tree topology implies that dsRNA viruses evolved from +RNA viruses on at least two independent occasions, whereas −RNA viruses evolved from dsRNA viruses. Reconstruction of RNA virus evolution using the RdRp tree as the scaffold suggests that the last common ancestors of the major branches of +RNA viruses encoded only the RdRp and a single jelly-roll capsid protein. Subsequent evolution involved independent capture of additional genes, in particular, those encoding distinct RNA helicases, enabling replication of larger RNA genomes and facilitating virus genome expression and virus-host interactions. Phylogenomic analysis reveals extensive gene module exchange among diverse viruses and horizontal virus transfer between distantly related hosts. Although the network of evolutionary relationships within the RNA virome is bound to further expand, the present results call for a thorough reevaluation of the RNA virus taxonomy.IMPORTANCEThe majority of the diverse viruses infecting eukaryotes have RNA genomes, including numerous human, animal, and plant pathogens. Recent advances of metagenomics have led to the discovery of many new groups of RNA viruses in a wide range of hosts. These findings enable a far more complete reconstruction of the evolution of RNA viruses than was attainable previously. This reconstruction reveals the relationships between different Baltimore classes of viruses and indicates extensive transfer of viruses between distantly related hosts, such as plants and animals. These results call for a major revision of the existing taxonomy of RNA viruses.


2019 ◽  
Author(s):  
Joseph L. DeRisi ◽  
Greg Huber ◽  
Amy Kistler ◽  
Hanna Retallack ◽  
Michael Wilkinson ◽  
...  

ABSTRACTNarnaviruses have been described as positive-sense RNA viruses with a remarkably simple genome of ∼ 3 kb, encoding only a highly conserved RNA-dependent RNA polymerase (RdRp). Many narnaviruses, however, are ‘ambigrammatic’ and harbour an additional uninterrupted open reading frame (ORF) covering almost the entire length of the reverse complement strand. No function has been described for this ORF, yet the absence of stops is conserved across diverse narnaviruses, and in every case the codons in the reverse ORF and the RdRp are aligned. The > 3 kb ORF overlap on opposite strands, unprecedented among RNA viruses, motivates an exploration of the constraints imposed or alleviated by the codon alignment. Here, we show that only when the codon frames are aligned can all stop codons be eliminated from the reverse strand by synonymous single-nucleotide substitutions in the RdRp gene, suggesting a mechanism for de novo gene creation within a strongly conserved amino-acid sequence. It will be fascinating to explore what implications this coding strategy has for other aspects of narnavirus biology. Beyond narnaviruses, our rapidly expanding catalogue of viral diversity may yet reveal additional examples of this broadly-extensible principle for ambigrammatic-sequence development.


2018 ◽  
Vol 46 (11) ◽  
pp. 5776-5791 ◽  
Author(s):  
Will McIntyre ◽  
Rachel Netzband ◽  
Gaston Bonenfant ◽  
Jason M Biegel ◽  
Clare Miller ◽  
...  
Keyword(s):  

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shinji Honda ◽  
Ana Eusebio-Cope ◽  
Shuhei Miyashita ◽  
Ayumi Yokoyama ◽  
Annisa Aulia ◽  
...  

Abstract The filamentous fungus Neurospora crassa is used as a model organism for genetics, developmental biology and molecular biology. Remarkably, it is not known to host or to be susceptible to infection with any viruses. Here, we identify diverse RNA viruses in N. crassa and other Neurospora species, and show that N. crassa supports the replication of these viruses as well as some viruses from other fungi. Several encapsidated double-stranded RNA viruses and capsid-less positive-sense single-stranded RNA viruses can be experimentally introduced into N. crassa protoplasts or spheroplasts. This allowed us to examine viral replication and RNAi-mediated antiviral responses in this organism. We show that viral infection upregulates the transcription of RNAi components, and that Dicer proteins (DCL-1, DCL-2) and an Argonaute (QDE-2) participate in suppression of viral replication. Our study thus establishes N. crassa as a model system for the study of host-virus interactions.


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