The Mutation Rate of Influenza Virus

[摘要] Influenza virus continues to be a major worldwide human health problem because it rapidly evolves antigenic changes and resistance to antiviral drugs. This rapid evolution is a consequence of the virus’ high mutation rate, which generates high genetic diversity and promotes adaptation. Most of these genetic variants, though, have a decreased ability to infect and replicate. Therefore, high mutation rates are a double-edged sword, providing abundant raw genetic changes for selection to act upon while burdening the viral population with low fitness members. My dissertation focuses on precisely characterizing influenza’s mutation rate, investigating the viral consequences of increasing the mutation rate, and describing mechanisms that allow influenza to tolerate increased mutation rates. I developed a novel assay that has permitted the first ever complete characterization of influenza’s mutational spectrum. Using this assay, I determined that overall mutation rates are similar between evolutionarily divergent viruses but that the rates of individual mutation classes can differ. I also found that the range of temperatures that influenza encounters within the human respiratory tract does not affect the mutation rate of a mammalian-adapted influenza strain in an MDCK cell culture system. To test the effect of an increased mutation rate, I treated influenza with the mutagenic nucleoside analogs, ribavirin, 5-azacytidine, and 5-fluorouracil. I found that each increases the mutation rate in a characteristic way. Influenza virus is intolerant of these changes, due to an increased production of genomes carrying detrimental mutations. Evolving influenza in low concentrations of nucleoside analogs failed to select for population-wide resistance but did select for two low frequency polymerase mutants (PB1 T123A and PA T97I) that were resistant to 5-fluorouracil. Both polymerase mutants mediate resistance the through maintenance of high genome synthesis upon 5-fluorouracil treatment. Additionally, I found that PB1 T123A has a fidelity phenotype that prevents the characteristic increase in C to U mutations by 5-fluorouracil. My work has led to the first full description of influenza’s mutation rate. It has also provided valuable new insights into how influenza is affected by and tolerates high mutation rates. These results have important implications for our understanding of influenza evolution.

[发布机构] University of Michigan

[效力级别] influenza virus

[关键词] mutation rates;influenza virus;Microbiology and Immunology;Science;Microbiology & Immunology