Coxsackievirus B3 mutator strains are attenuated in vivo
| Autor: | Hervé Blanc, Stéphanie Beaucourt, Nina F. Gnädig, Grace Campagnola, Antonio V. Bordería, Marta Sanz-Ramos, Peng Gong, Olve B. Peersen, Marco Vignuzzi |
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| Přispěvatelé: | Populations virales et Pathogenèse, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Department of Biochemistry and Molecular Biology, Colorado State University [Fort Collins] (CSU), his work was supported by National Insti- tutes of Health Grant AI-059130 (to O.B.P.), a Medical and Health Research grant from the City of Paris (to M.V.), and the European Community's Seventh Framework Programme under Grant PIRG-GA-2008-239321 (to M.V.). A.V.B. was supported by French National Grant ANR-09-JCJC-0118-1, and M.V. was supported by European Research Council Starting Grant Project 242719., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Models Molecular Molecular Conformation MESH: Base Sequence medicine.disease_cause Mice chemistry.chemical_compound RNA polymerase MESH: Animals MESH: Genetic Variation MESH: Models Genetic Mutation frequency Polymerase Genetics Mice Inbred C3H 0303 health sciences Mutation Multidisciplinary biology MESH: Kinetics Enterovirus B Human 3. Good health MESH: Mutagenesis Site-Directed Phenotype PNAS Plus [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology MESH: RNA Replicase MESH: Models Molecular MESH: Mutation Molecular Sequence Data RNA-dependent RNA polymerase MESH: Phenotype Catalysis Virus 03 medical and health sciences medicine Animals MESH: Mice Inbred C3H MESH: Mice 030304 developmental biology MESH: Molecular Conformation MESH: Molecular Sequence Data Base Sequence Models Genetic 030306 microbiology Genetic Variation RNA RNA-Dependent RNA Polymerase MESH: Catalysis Virology MESH: Male Kinetics Viral replication chemistry MESH: Enterovirus B Human Mutagenesis Site-Directed biology.protein |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2012, 109 (34), pp.E2294-303. ⟨10.1073/pnas.1204022109⟩ Proceedings of the National Academy of Sciences of the United States of America, 2012, 109 (34), pp.E2294-303. ⟨10.1073/pnas.1204022109⟩ Proceedings of the National Academy of Sciences |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.1204022109⟩ |
| Popis: | International audience; Based on structural data of the RNA-dependent RNA polymerase, rational targeting of key residues, and screens for Coxsackievirus B3 fidelity variants, we isolated nine polymerase variants with mutator phenotypes, which allowed us to probe the effects of lowering fidelity on virus replication, mutability, and in vivo fitness. These mutator strains generate higher mutation frequencies than WT virus and are more sensitive to mutagenic treatments, and their purified polymerases present lower-fidelity profiles in an in vitro incorporation assay. Whereas these strains replicate with WT-like kinetics in tissue culture, in vivo infections reveal a strong correlation between mutation frequency and fitness. Variants with the highest mutation frequencies are less fit in vivo and fail to productively infect important target organs, such as the heart or pancreas. Furthermore, whereas WT virus is readily detectable in target organs 30 d after infection, some variants fail to successfully establish persistent infections. Our results show that, although mutator strains are sufficiently fit when grown in large population size, their fitness is greatly impacted when subjected to severe bottlenecking, which would occur during in vivo infection. The data indicate that, although RNA viruses have extreme mutation frequencies to maximize adaptability, nature has fine-tuned replication fidelity. Our work forges ground in showing that the mutability of RNA viruses does have an upper limit, where larger than natural genetic diversity is deleterious to virus survival. |
| Databáze: | OpenAIRE |
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