The not-so-infinite malleability of RNA viruses: Viral and cellular determinants of RNA virus mutation rates

Smith, Everett Clinton

doi:10.1371/journal.ppat.1006254

Cited by 38 publications

(32 citation statements)

References 27 publications

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“…Compared to previous coronavirus epidemics, such as MERS and SARS, more than 50 % of COVID-19 infections can be attributed to asymptomatic and presymptomatic transmission, thereby accelerating its transmission capacity [ 8 ]. As SARS-CoV-2 can use the furin enzyme in the host to cut the S protein, mutations and recombination events occur rather frequently [ 9 , 10 ]. The mutated SARS-CoV-2 is constantly adapting to the human host [ 1 ], causing a lung invasion rate of 100 to 1,000 times that of SARS [ 11 ].…”

Section: Covid-19mentioning

confidence: 99%

The direct evidence and mechanism of traditional Chinese medicine treatment of COVID-19

Zhang

Duan

et al. 2021

Biomedicine & Pharmacotherapy

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Section: Covid-19mentioning

confidence: 99%

The direct evidence and mechanism of traditional Chinese medicine treatment of COVID-19

Zhang

Duan

et al. 2021

Biomedicine & Pharmacotherapy

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“…Moreover, virus-specific factors such as mutation and reassortment may also contribute to the ability of BTV to invade new regions or cause disease outbreaks in otherwise enzootic areas. The BTV genome is replicated via an RNA-dependent RNA polymerase, which—as with other RNA viruses—lacks proof-reading ability and thus generates more replication errors during transcription [ 7 , 8 , 9 ]. For many RNA viruses, this is considered an important mechanism contributing to genetic diversification and overall fitness; the mutation rate and replication rate strike a delicate balance, allowing these viruses to rapidly adapt through the generation of large viral populations [ 8 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Reassortment between Endemic Bluetongue Viruses Features Global Shifts in Segment Frequencies and Preferred Segment Combinations

et al. 2021

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Bluetongue virus (BTV) is an arthropod-borne pathogen that is associated with sometimes severe disease in both domestic and wild ruminants. Predominantly transmitted by Culicoides spp. biting midges, BTV is composed of a segmented, double-stranded RNA genome. Vector expansion and viral genetic changes, such as reassortment between BTV strains, have been implicated as potential drivers of ongoing BTV expansion into previously BTV-free regions. We used an in vitro system to investigate the extent and flexibility of reassortment that can occur between two BTV strains that are considered enzootic to the USA, BTV-2 and BTV-10. Whole genome sequencing (WGS) was coupled with plaque isolation and a novel, amplicon-based sequencing approach to quantitate the viral genetic diversity generated across multiple generations of in vitro propagation. We found that BTV-2 and BTV-10 were able to reassort across multiple segments, but that a preferred BTV-2 viral backbone emerged in later passages and that certain segments were more likely to be found in reassortant progeny. Our findings indicate that there may be preferred segment combinations that emerge during BTV reassortment. Moreover, our work demonstrates the usefulness of WGS and amplicon-based sequencing approaches to improve understanding of the dynamics of reassortment among segmented viruses such as BTV.

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“…The mechanisms for emergence of pathogens from enzootic flaviviruses are not clear despite past examples of large-scale epidemics caused by under-studied flaviviruses such as Zika virus [4]. The emergence of flaviviruses as pathogens may be linked to the naturally high rate of mutations in the genome of RNA viruses, due to the low proof-reading efficiency of the RNA-dependent RNA polymerase [5]. Indeed, flaviviruses are positive-sense, single-stranded RNA viruses with a genome of approximately 11 kilobases (kb), contained in an enveloped icosahedral nucleocapsid [6,7].…”

Section: Introductionmentioning

confidence: 99%

NS4/5 mutations enhance flavivirus Bamaga virus infectivity and pathogenicity in vitro and in vivo

et al. 2020

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Flaviviruses such as yellow fever, dengue or Zika viruses are responsible for significant human and veterinary diseases worldwide. These viruses contain an RNA genome, prone to mutations, which enhances their potential to emerge as pathogens. Bamaga virus (BgV) is a mosquito-borne flavivirus in the yellow fever virus group that we have previously shown to be host-restricted in vertebrates and horizontally transmissible by Culex mosquitoes. Here, we aimed to characterise BgV host-restriction and to investigate the mechanisms involved. We showed that BgV could not replicate in a wide range of vertebrate cell lines and animal species. We determined that the mechanisms involved in BgV host-restriction were independent of the type-1 interferon response and RNAse L activity. Using a BgV infectious clone and two chimeric viruses generated as hybrids between BgV and West Nile virus, we demonstrated that BgV host-restriction occurred post-cell entry. Notably, BgV host-restriction was shown to be temperature-dependent, as BgV replicated in all vertebrate cell lines at 34˚C but only in a subset at 37˚C. Serial passaging of BgV in Vero cells resulted in adaptive mutants capable of efficient replication at 37˚C. The identified mutations resulted in amino acid substitutions in NS4A-S124F, NS4B-N244K and NS5-G2C, all occurring close to a viral protease cleavage site (NS4A/2K and NS4B/NS5). These mutations were reverse engineered into infectious clones of BgV, which revealed that NS4B-N244K and NS5-G2C were sufficient to restore BgV replication in vertebrate cells at 37˚C, while NS4A-S124F further increased replication efficiency. When these mutant viruses were injected into immunocompetent mice, alongside BgV and West Nile virus chimeras, infection and neurovirulence were enhanced as determined by clinical scores, seroconversion, microneutralisation, viremia, histopathology and immunohistochemistry, confirming the involvement of these residues in the attenuation of BgV. Our studies identify a new mechanism of host-restriction and attenuation of a mosquito-borne flavivirus.

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The not-so-infinite malleability of RNA viruses: Viral and cellular determinants of RNA virus mutation rates

Cited by 38 publications

References 27 publications

The direct evidence and mechanism of traditional Chinese medicine treatment of COVID-19

The direct evidence and mechanism of traditional Chinese medicine treatment of COVID-19

In Vitro Reassortment between Endemic Bluetongue Viruses Features Global Shifts in Segment Frequencies and Preferred Segment Combinations

NS4/5 mutations enhance flavivirus Bamaga virus infectivity and pathogenicity in vitro and in vivo

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