RESUMO
RNA viruses, such as poliovirus, have a great evolutionary capacity, allowing them to quickly adapt and overcome challenges encountered during infection. Here we show that poliovirus infection in immune-competent mice requires adaptation to tissue-specific innate immune microenvironments. The ability of the virus to establish robust infection and virulence correlates with its evolutionary capacity. We further identify a region in the multi-functional poliovirus protein 2B as a hotspot for the accumulation of minor alleles that facilitate a more effective suppression of the interferon response. We propose that population genetic dynamics enables poliovirus spread between tissues through optimization of the genetic composition of low frequency variants, which together cooperate to circumvent tissue-specific challenges. Thus, intrahost virus evolution determines pathogenesis, allowing a dynamic regulation of viral functions required to overcome barriers to infection.RNA viruses, such as polioviruses, have a great evolutionary capacity and can adapt quickly during infection. Here, the authors show that poliovirus infection in mice requires adaptation to innate immune microenvironments encountered in different tissues.
Assuntos
Imunidade Inata/imunologia , Especificidade de Órgãos/imunologia , Poliomielite/imunologia , Poliovirus/imunologia , Animais , Antivirais/farmacologia , Células COS , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Evolução Molecular , Perfilação da Expressão Gênica/métodos , Células HeLa , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Interferons/farmacologia , Camundongos Knockout , Camundongos Transgênicos , Mutação , Especificidade de Órgãos/efeitos dos fármacos , Especificidade de Órgãos/genética , Poliomielite/genética , Poliomielite/virologia , Poliovirus/genética , Poliovirus/patogenicidade , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia , Virulência/genética , Virulência/imunologiaRESUMO
Mutation and recombination are central processes driving microbial evolution. A high mutation rate fuels adaptation but also generates deleterious mutations. Recombination between two different genomes may resolve this paradox, alleviating effects of clonal interference and purging deleterious mutations. Here we demonstrate that recombination significantly accelerates adaptation and evolution during acute virus infection. We identified a poliovirus recombination determinant within the virus polymerase, mutation of which reduces recombination rates without altering replication fidelity. By generating a panel of variants with distinct mutation rates and recombination ability, we demonstrate that recombination is essential to enrich the population in beneficial mutations and purge it from deleterious mutations. The concerted activities of mutation and recombination are key to virus spread and virulence in infected animals. These findings inform a mathematical model to demonstrate that poliovirus adapts most rapidly at an optimal mutation rate determined by the trade-off between selection and accumulation of detrimental mutations.