IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon


Alphaviruses represent a group of highly important human pathogens, which are transmitted by mosquito vectors between vertebrate hosts. Alphavirus replication in vertebrates depends on their ability to interfere with host antiviral responses on both cellular and organismal levels. The identification of cellular factors, which affect virus replication, and characterization of their functions may prove crucial for the design of new effective vaccine candidates. We have demonstrated that the protein product of one of the interferon-stimulated genes, IFIT1, is a potent inhibitor of translation of the incoming alphavirus genomes and ultimately, virus replication. The secondary structure of the 5’untranslated regions (5’UTRs) of alphavirus genomes was shown to play a critical role in alphavirus resistance to this inhibitory effect. Moreover, in IFIT1-expressing cells, wt alphaviruses exhibiting low sensitivity to IFIT1 also were found to induce high levels of type I IFN. Altogether, our data show that alphavirus 5’UTRs were evolutionarily selected to meet the requirements of both functioning as promoters for positive- and negative-strand RNA synthesis and supporting the resistance to inhibitory effects of IFIT1. We further exploited this new knowledge to develop mutated alphaviruses, which displayed higher sensitivity to IFIT1 and more attenuated phenotypes.


Vyšlo v časopise: IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon. PLoS Pathog 11(4): e32767. doi:10.1371/journal.ppat.1004863
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1004863

Souhrn

Alphaviruses represent a group of highly important human pathogens, which are transmitted by mosquito vectors between vertebrate hosts. Alphavirus replication in vertebrates depends on their ability to interfere with host antiviral responses on both cellular and organismal levels. The identification of cellular factors, which affect virus replication, and characterization of their functions may prove crucial for the design of new effective vaccine candidates. We have demonstrated that the protein product of one of the interferon-stimulated genes, IFIT1, is a potent inhibitor of translation of the incoming alphavirus genomes and ultimately, virus replication. The secondary structure of the 5’untranslated regions (5’UTRs) of alphavirus genomes was shown to play a critical role in alphavirus resistance to this inhibitory effect. Moreover, in IFIT1-expressing cells, wt alphaviruses exhibiting low sensitivity to IFIT1 also were found to induce high levels of type I IFN. Altogether, our data show that alphavirus 5’UTRs were evolutionarily selected to meet the requirements of both functioning as promoters for positive- and negative-strand RNA synthesis and supporting the resistance to inhibitory effects of IFIT1. We further exploited this new knowledge to develop mutated alphaviruses, which displayed higher sensitivity to IFIT1 and more attenuated phenotypes.


Zdroje

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