日時：	2018年10月31日 15：00～16：00
場所：	京都大学ウイルス再生研2号館（旧ウイルス研本館）1階セミナー室
演者：	Sam J Wilson Ph.D. ( Principal Investigator MRC - University of Glasgow Centre for Virus Research)
演題：	Dissection and Evolution of the ‘Antiviral State’

講演要旨

The host innate immune response mediated by type I interferons (IFNs) and the resulting up-regulation of hundreds of interferon-stimulated genes (ISGs) provides an immediate barrier against virus infection. Studies of the type I ‘interferome’ (the transcriptional response to interferons) have mainly been carried out at a single species level, often lacking the power necessary to understand key evolutionary features of this pathway. Using a single experimental platform, we determined the properties of the interferomes of multiple vertebrate species. This approach revealed a conserved ‘core’ of 62 ISGs that have retained IFN stimulation for over 300 million years. As well as antiviral genes, this approach defined multiple ancestral functions of the vertebrate interferome. In addition, analysis of genes commonly downregulated by IFNs suggests that epigenetic regulation of transcription is a fundamental aspect of the IFN response.

 

The key role that the interferome plays in sculpting susceptibility to infection, and the severity of disease, has placed unique and extreme evolutionary pressures on this subset of genes. We observed that ISGs are more likely to be positively selected and that duplications/expansions of ISGs are often beneficial to the host. Because viral RNAs are frequently targeted by the ‘antiviral state’, we hypothesized that the mRNAs of highly upregulated ISGs might have evolved to avoid self-targeting by antiviral effectors. We report that the nucleotide composition of ISGs is significantly different from that of the genome as a whole and is strikingly different from genes whose expression is downregulated in response to IFN, referred to as IFN repressed genes (IRGs). Interestingly, this compositional bias appears to be a general feature of vertebrate interferomes and is present in multiple species. Following knock out of a single RNA-targeting ISG, we observed a reduction in the number of IRGs following IFN stimulation. We suggest that the decreased mRNA abundance of IRGs might simply represent ‘collateral damage’ from the RNA-targeting components of the antiviral state. Moreover, we speculate that ISGs have evolved to occupy an unusual compositional space to avoid self-targeting by the antiviral effectors.

 

Building on our transcriptomic analyses of the interferome, we have expanded and refined our arrayed expression libraries of ISGs. We describe the utility of these ISG libraries from multiple vertebrates as a method for antiviral gene discovery.                               （言語：英語　/ Language : English）

 

 

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