Extinction of Zika Virus and Usutu Virus by Lethal Mutagenesis Reveals Different Patterns of Sensitivity to Three Mutagenic Drugs
| Autor: | Raquel Navarro Sempere, Charlotta Polacek, Prashansa Meyn, Armando Arias, Maria Rosaria Bassi |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mutagenesis (molecular biology technique) Mutation frequency Favipiravir Virus Replication Antiviral Agents Virus Zika virus Cell Line 03 medical and health sciences SDG 3 - Good Health and Well-being Mutation Rate Error threshold Serial passage Chlorocebus aethiops Ribavirin Animals 5-fluorouracil Lethal mutagenesis Pharmacology (medical) Usutu virus Serial Passage Vero Cells Pharmacology Infectivity biology Zika Virus Infection Flavivirus Epithelial Cells Nucleosides Zika Virus biology.organism_classification Virology Amides 030104 developmental biology Infectious Diseases Mutagenesis Pyrazines Fluorouracil Ribonucleosides Mutagens |
| Zdroj: | Bassi, M R, Sempere, R N, Meyn, P, Polacek, C & Arias, A 2018, ' Extinction of zika virus and usutu virus by lethal mutagenesis reveals different patterns of sensitivity to three mutagenic drugs ', Antimicrobial Agents and Chemotherapy, vol. 62, no. 9, e00380-18 . https://doi.org/10.1128/AAC.00380-18 |
| ISSN: | 1098-6596 |
| DOI: | 10.1128/AAC.00380-18 |
| Popis: | Flaviviruses constitute an increasing source of public health concern, with growing numbers of pathogens causing disease and geographic spread to temperate climates. Despite a large body of evidence supporting mutagenesis as a conceivable antiviral strategy, there are currently no data on the sensitivity to increased mutagenesis for Zika virus (ZIKV) and Usutu virus (USUV), two emerging flaviviral threats. In this study, we demonstrate that both viruses are sensitive to three ribonucleosides, favipiravir, ribavirin, and 5-fluorouracil, that have shown mutagenic activity against other RNA viruses while remaining unaffected by a mutagenic deoxyribonucleoside. Serial cell culture passages of ZIKV in the presence of these compounds resulted in the rapid extinction of infectivity, suggesting elevated sensitivity to mutagenesis. USUV extinction was achieved when a 10-fold dilution was applied between every passage, but not in experiments involving undiluted virus, indicating an overall lower susceptibility than ZIKV. Although the two viruses are inhibited by the same three drugs, ZIKV is relatively more susceptive to serial passage in the presence of purine analogues (favipiravir and ribavirin), while USUV replication is suppressed more efficiently by 5-fluorouracil. These differences in sensitivity typically correlate with the increases in the mutation frequencies observed in each nucleoside treatment. These results are relevant to the development of efficient therapies based on lethal mutagenesis and support the rational selection of different mutagenic nucleosides for each pathogen. We will discuss the implications of these results to the fidelity of flavivirus replication and the design of antiviral therapies based on lethal mutagenesis. |
| Databáze: | OpenAIRE |
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