IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon.
Alphaviruses are a group of widely distributed human and animal pathogens. It is well established that their replication is sensitive to type I IFN treatment, but the mechanism of IFN inhibitory function remains poorly understood. Using a new experimental system, we demonstrate that in the presence of IFN-β, activation of interferon-stimulated genes (ISGs) does not interfere with either attachment of alphavirus virions to the cells, or their entry and nucleocapsid disassembly. However, it strongly affects translation of the virion-delivered virus-specific RNAs. One of the ISG products, IFIT1 protein, plays a major role in this translation block, although an IFIT1-independent mechanism is also involved. The 5'UTRs of the alphavirus genomes were found to differ significantly in their ability to drive translation in the presence of increased concentration of IFIT1. Prior studies have shown that adaptation of naturally circulating alphaviruses to replication in tissue culture results in accumulation of mutations in the 5'UTR, which increase the efficiency of the promoter located in the 5'end of the genome. Here, we show that these mutations also decrease resistance of viral RNA to IFIT1-induced translation inhibition. In the presence of higher levels of IFIT1, alphaviruses with wt 5'UTRs became potent inducers of type I IFN, suggesting a new mechanism of type I IFN induction. We applied this knowledge of IFIT1 interaction with alphaviruses to develop new attenuated variants of Venezuelan equine encephalitis and chikungunya viruses that are more sensitive to the antiviral effects of IFIT1, and thus could serve as novel vaccine candidates.
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Josephine M
JM
Reynaud
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Dal Young
DY
Kim
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Svetlana
S
Atasheva
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Aliaksandra
A
Rasalouskaya
Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
James P
JP
White
Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America; Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, Missouri, United States of America; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Michael S
MS
Diamond
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America; Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Scott C
SC
Weaver
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Elena I
EI
Frolova
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Ilya
I
Frolov
D020121:5' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D000330:Aedes; D000524:Alphavirus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002646:Chikungunya virus / Q000235:genetics / Q000276:immunology / Q000502:physiology; D015536:Down-Regulation; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics / Q000276:immunology / Q000502:physiology; D005657:Fungal Vaccines / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D054884:Host-Pathogen Interactions; D007370:Interferon Type I / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D009154:Mutation; D041681:NIH 3T3 Cells; D012313:RNA / Q000378:metabolism; D016601:RNA-Binding Proteins; D056189:Viral Tropism; D014779:Virus Replication
D020121:5' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D005657:Fungal Vaccines; C092573:Ifit1 protein, mouse; D007370:Interferon Type I; C039919:RNA, recombinant; D016601:RNA-Binding Proteins; D012313:RNA