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. 2009 Jun 18;4(6):e5969.
doi: 10.1371/journal.pone.0005969.

Patterns of oligonucleotide sequences in viral and host cell RNA identify mediators of the host innate immune system

Benjamin D Greenbaum  1 , Raul Rabadan, Arnold J Levine
Affiliations

Patterns of oligonucleotide sequences in viral and host cell RNA identify mediators of the host innate immune system

Benjamin D Greenbaum et al. PLoS One. .

Abstract

The innate immune response provides a first line of defense against pathogens by targeting generic differential features that are present in foreign organisms but not in the host. These innate responses generate selection forces acting both in pathogens and hosts that further determine their co-evolution. Here we analyze the nucleic acid sequence fingerprints of these selection forces acting in parallel on both host innate immune genes and ssRNA viral genomes. We do this by identifying dinucleotide biases in the coding regions of innate immune response genes in plasmacytoid dendritic cells, and then use this signal to identify other significant host innate immune genes. The persistence of these biases in the orthologous groups of genes in humans and chickens is also examined. We then compare the significant motifs in highly expressed genes of the innate immune system to those in ssRNA viruses and study the evolution of these motifs in the H1N1 influenza genome. We argue that the significant under-represented motif pattern of CpG in an AU context--which is found in both the ssRNA viruses and innate genes, and has decreased throughout the history of H1N1 influenza replication in humans--is immunostimulatory and has been selected against during the co-evolution of viruses and host innate immune genes. This shows how differences in host immune biology can drive the evolution of viruses that jump into species with different immune priorities than the original host.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Comparison of CpG Content for human and mouse CDS regions.
A) CpG odds ratio (η) versus C+G content for CDS regions of all human genes. The genes for Type I interferons are highlighted in red. B) CpG odds ratio (η) versus C+G content for CDS regions of all mouse genes. The genes for Type I interferons are highlighted in red. C) Standardized histogram of differences between CpG frequency for CDS regions in human versus mouse genes.
Figure 2
Figure 2. CpG bias in pDC expression vs CDS region CpG Content.
A) log2 of the ratio of CpG stimulated pDC expression levels to control expression level vs. CpG frequency. B) log2 of the ratio of CpG stimulated pDC expression levels to control expression level vs. ApT frequency.
Figure 3
Figure 3. Evolution of the CpG frequency of H1N1 influenza A virus in time, binned by CpG context for the following four sets of bins:
A) CpGs “protected” by Cs and Gs. B) CpGs surrounded by As and Us. C) CpGs with a C or G on the right and an A or U on the left. D) CpGs with a C or G on the left and an A or U on the right. E) In contrast, this figure shows GpCs surrounded by As and Us. There is no decline as observed in (B).
See this image and copyright information in PMC

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