Evolution and mimicry in influenza and other RNA viruses

It is known that CpG dinucleotides are under-represented in the genomic DNA of many vertebrates. This is commonly believed to be from the methylation of cytosine residues in this dinucleotide and the corresponding high rate of deamination of 5-methycytosine, which lowers the frequency of this dinucleotide in DNA. Surprisingly, many ssRNA viruses that infect these vertebrate hosts also have a low CG content in their genomes. Viruses are obligate intracellular parasites whose evolution is inexorably linked to the nature and fate of its host. One expects that virus and host genomes should have common features. I will describe recent work where we compared evolutionary patterns in the genomes of ssRNA viruses and their hosts. we find that specific dinucleotide patterns are pervasively over- or under-represented in many RNA viruses and their hosts, suggesting that these viruses evolve by mimicking some of the features of their host’s gennomes (DNA) and likely also their corresponding mRNAs. When a virus crosses a species barrier into a different host, the pressure to replicate, survive and adapt 
leaves a footprint in dinucleotide frequencies as a function of time. For instance, since human genes seem to be under higher pressure to eliminate CpG dinucleotide motifs than avian genes, this pressure might be reflected in the genomes of human viruses (DNA and RNA viruses) when compared to those of the same viruses replicating in avian hosts. To test this idea we analyzed the evolution of the influenza virus since 1918. We find that the influenza A virus, which originated from an avian reservoir and has been replicating in humans over many generations, evolves in a direction strongly selected to reduce the frequency of CpG dinucleotides in its genome. Consistent with this observation, we find that the influenza B virus, which has spent much more time in the human population, has adapted better to its human host and exhibits an extremely low CpG content. We propose that overrepresented viral CG motifs are recognized by Toll-like receptors TLR7/TLR8/TLR9 in a context specific manner and are responsible for the "Cytokine Storm" that leads to high mortality rates in pandemics, such as the 1918 Spanish Flu and the more recent H5N1 and H1N1mini pandemics. In follow up work, our proposal was validated in mouse plasmacytoid dendritic (PDc)cells by showing that when activated by specific oligonucleotide sequences, they produce IFN which activates NK T-cells.