Extinction of Zika Virus and Usutu Virus by Lethal Mutagenesis Reveals Different Patterns of Sensitivity to Three Mutagenic Drugs

Bassi, Maria Rosaria; Sempere, Raquel Navarro; Meyn, Prashansa; Polacek, Charlotta; Arias, Armando

doi:10.1128/aac.00380-18

Cited by 34 publications

(42 citation statements)

References 103 publications

(144 reference statements)

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“…This molecule, along with another purine analog (ribavirin) and 5-fluorouracil (a pyrimidine analog), led to sustained decreases in virus titers but not to complete viral extinction in Vero cell supernatant media. In the same study, ZIKV was inhibited more efficiently by ribavirin and favipiravir, while USUV replication was affected to a greater extent by 5-fluorouracil [ 78 ]. Similarly, a 10-day exposure to favipiravir, ribavirin, or a combination of both drugs could lead to the complete extinction of infectivity and vRNA in the cell-culture supernatant media but not inside Vero cells persistently infected with USUV.…”

Section: In Vitro Modelsmentioning

confidence: 99%

In Vitro and In Vivo Models to Study the Zoonotic Mosquito-Borne Usutu Virus

Benzarti

Garigliany

2020

Viruses

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Usutu virus (USUV), a mosquito-borne zoonotic flavivirus discovered in South Africa in 1959, has spread to many European countries over the last 20 years. The virus is currently a major concern for animal health due to its expanding host range and the growing number of avian mass mortality events. Although human infections with USUV are often asymptomatic, they are occasionally accompanied by neurological complications reminiscent of those due to West Nile virus (another flavivirus closely related to USUV). Whilst USUV actually appears less threatening than some other emergent arboviruses, the lessons learned from Chikungunya, Dengue, and Zika viruses during the past few years should not be ignored. Further, it would not be surprising if, with time, USUV disperses further eastwards towards Asia and possibly westwards to the Americas, which may result in more pathogenic USUV strains to humans and/or animals. These observations, inviting the scientific community to be more vigilant about the spread and genetic evolution of USUV, have prompted the use of experimental systems to understand USUV pathogenesis and to boost the development of vaccines and antivirals. This review is the first to provide comprehensive coverage of existing in vitro and in vivo models for USUV infection and to discuss their contribution in advancing data concerning this neurotropic virus. We believe that this paper is a helpful tool for scientists to identify gaps in the knowledge about USUV and to design their future experiments to study the virus.

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Section: In Vitro Modelsmentioning

confidence: 99%

In Vitro and In Vivo Models to Study the Zoonotic Mosquito-Borne Usutu Virus

Benzarti

Garigliany

2020

Viruses

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“…Bizarre neurological manifestations were also observed in patients infected by Ntaya virus (NTAV) 82 , a neurotropic virus from the Japanese encephalitis serocomplex, as well as WNV in humans 83,84 and in mice 85 , USUV 86,87 and DENV 88,89 . The fact that these viruses line up more on the positive side of the opening energy plots in Fig.…”

Section: Discussionmentioning

confidence: 99%

Musashi binding elements in Zika and related Flavivirus 3’UTRs: A comparative studyin silico

Schneider

Wolfinger

2018

Preprint

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Zika virus (ZIKV) belongs to a class of neurotropic viruses that have the ability to cause congenital infection, which can result in microcephaly or fetal demise. Recently, the RNA-binding protein Musashi-1 (Msi1), which mediates the maintenance and self-renewal of stem cells and acts as a translational regulator, has been associated with promoting ZIKV replication, neurotropism, and pathology. Msi1 predominantly binds to single-stranded motifs in the 3' untranslated region (UTR) of RNA that contain a UAG trinucleotide in their core. We systematically analyzed the properties of Musashi binding elements (MBEs) in the 3'UTR of flaviviruses with a thermodynamic model for RNA folding. Our results indicate that MBEs in ZIKV 3'UTRs occur predominantly in unpaired, single-stranded structural context, thus corroborating experimental observations by a biophysical model of RNA structure formation. Statistical analysis and comparison with related viruses show that ZIKV MBEs are maximally accessible among mosquito-borne flaviviruses. Our study addresses the broader question of whether other emerging arboviruses can cause similar neurotropic effects through the same mechanism in the developing fetus by establishing a link between the biophysical properties of viral RNA and teratogenicity. Moreover, our thermodynamic model can explain recent experimental findings and predict the Msi1-related neurotropic potential of other viruses. 2/15

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“…Indeed, only few reports investigated antiviral drugs against USUV. In addition to interferons, which were shown to be active against USUV [45], other compounds include: Ribavirin (RBV), favipiravir (FAV), 5-fluorouracil (FU) and 2'-C-methyl nucleoside analogs such as 2'-Cmethyladenosine (2'CMA) that elicit antiviral activity towards USUV at 10-100 uM with a low selective index [46,47], Hypolipidemic drugs targeting the Acetyl Coenzyme A Carboxylase such as the 5-(tetradecyloxy)-2-furoic acid (TOFA) or 3,3,14,14-tetramethylhexadecanedioic acid MEDICA 16 [48] or the autophagy inhibitors 3-methyladenine and wortmanin that significantly reduced USUV replication in Vero cells [49]. Although HeE1-2Y and HeE1-17Y compounds were tested only for one USUV strain, it is expected that they will be active also for other circulating strains because of the little genetic variation among isolates observed so far [50,51].…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Comprehensive response to Usutu virus following first isolation in blood donors in the Friuli Venezia Giulia region of Italy: Development of recombinant NS1-based serology and sensitivity to antiviral drugs

et al. 2020

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Surveillance of Usutu virus is crucial to prevent future outbreaks both in Europe and in other countries currently naïve to the infection, such as the Americas. This goal remains difficult to achieve, notably because of the lack of large-scale cohort studies and the absence of commercially available diagnostic reagents for USUV. This work started with the first identification of USUV in a blood donor in the Friuli Venezia Giulia (FVG) Region in Northern-Eastern Italy, which is endemic for West Nile virus. Considering that only one IgG ELISA is commercially available, but none for IgM, a novel NS1 antigen based IgG/M ELISA has been developed. This assay tested successfully for the detection of Usutu virus in blood donors with the identification of a second case of transmission and high levels of exposure. Furthermore, two pan-flavivirus antiviral drugs, that we previously characterized to be inhibitors of other flavivirus infectivity, were successfully tested for inhibition of Usutu virus with inhibitory concentrations in the low micromolar range. To conclude, this work identifies NorthEastern Italy as endemic for Usutu virus with implications for the screening of transfusion blood. A novel NS1-based ELISA test has been implemented for the detection of IgM/G that will be of importance as a tool for the diagnosis and surveillance of Usutu virus infection. Finally, Usutu virus is shown to be sensitive to a class of promising pan-flavivirus drugs.

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Extinction of Zika Virus and Usutu Virus by Lethal Mutagenesis Reveals Different Patterns of Sensitivity to Three Mutagenic Drugs

Cited by 34 publications

References 103 publications

In Vitro and In Vivo Models to Study the Zoonotic Mosquito-Borne Usutu Virus

In Vitro and In Vivo Models to Study the Zoonotic Mosquito-Borne Usutu Virus

Musashi binding elements in Zika and related Flavivirus 3’UTRs: A comparative studyin silico

Comprehensive response to Usutu virus following first isolation in blood donors in the Friuli Venezia Giulia region of Italy: Development of recombinant NS1-based serology and sensitivity to antiviral drugs

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