The codon usage of a influenza A virus gene originating from avian viruses adapts to the tRNA pools in interferon-induced human cells
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Influenza A virus infection causes a highly contagious annual respiratory disease in humans as well as periodic pandemics with higher mortality rates. Due to the segmented nature of influenza A virus’ negative-sense RNA genome, reassortment may occur between viruses infecting the same host cell, which generates new combinations of influenza A genomic segments within a single virion. Reassortment events between avian and human-infecting viruses have been a source of pandemic influenza A viruses in the past, and these lineages have stably switched to human hosts, causing seasonal epidemics in the human population. As different organisms display different patterns of synonymous codon usage, I expected that the codon usage of human-infecting avian origin influenza A viral genes would adapt over time to reflect codon usage found in humans. I found instead that the codon usage of the PB1 gene from the H3N2 lineage is adapting to be less like the presumed optimal codon usage as determined by CAI. Upon generating recombinant viruses displaying a PB1 codon usage more similar to modern viruses, there was no difference in growth in cell culture between viruses with early and modern patterns of codon usage. In interferon treated cells, however, viruses with a PB1 displaying modern codon usage patterns grew to a titer 10-fold higher than that of viruses with a PB1 with a codon usage similar to early viruses. This result implied that the codon usage of modern H3N2 PB1 genes is adaptive in interferon stimulated cells, but not in unstimulated cells, and that this adaptation may describe the differences in codon usage observed in PB1 across the H3N2 lineage. To test this hypothesis, I used TGIRT-seq to sequence the tRNA pools in both IFN-treated and untreated human A549 cells. In fact, my results show that over time, the codon usage of H3N2 PB1 proteins has been changing to more closely reflect the tRNA availability in IFN-treated cells. These results show that adaptation to the IFN- induced antiviral state has driven the changes in the codon usage of the PB1 protein of H3N2 viruses.