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Inhibition of Pyrimidine Biosynthesis Pathway Suppresses Viral Growth through Innate Immunity
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نویسنده
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lucas-hourani m. ,dauzonne d. ,jorda p. ,cousin g. ,lupan a. ,helynck o. ,caignard g. ,janvier g. ,andré-leroux g. ,khiar s. ,escriou n. ,desprès p. ,jacob y. ,munier-lehmann h. ,tangy f. ,vidalain p.-o.
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منبع
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plos pathogens - 2013 - دوره : 9 - شماره : 10
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چکیده
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Searching for stimulators of the innate antiviral response is an appealing approach to develop novel therapeutics against viral infections. here,we established a cell-based reporter assay to identify compounds stimulating expression of interferon-inducible antiviral genes. dd264 was selected out of 41,353 compounds for both its immuno-stimulatory and antiviral properties. while searching for its mode of action,we identified dd264 as an inhibitor of pyrimidine biosynthesis pathway. this metabolic pathway was recently identified as a prime target of broad-spectrum antiviral molecules,but our data unraveled a yet unsuspected link with innate immunity. indeed,we showed that dd264 or brequinar,a well-known inhibitor of pyrimidine biosynthesis pathway,both enhanced the expression of antiviral genes in human cells. furthermore,antiviral activity of dd264 or brequinar was found strictly dependent on cellular gene transcription,nuclear export machinery,and required irf1 transcription factor. in conclusion,the antiviral property of pyrimidine biosynthesis inhibitors is not a direct consequence of pyrimidine deprivation on the virus machinery,but rather involves the induction of cellular immune response. © 2013 lucas-hourani et al.
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آدرس
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institut pasteur,unité de génomique virale et vaccination,paris,france,cnrs,umr3569,paris, France, institut curie,centre de recherche,paris,france,cnrs,umr176,paris, France, institut curie,centre de recherche,paris,france,cnrs,umr176,paris, France, institut curie,centre de recherche,paris,france,cnrs,umr176,paris, France, institut pasteur,unité de chimie et biocatalyse,paris,france,cnrs,umr3523,paris,france,babes-bolyai university,department of chemistry,cluj-napoca, Romania, institut pasteur,unité de chimie et biocatalyse,paris,france,cnrs,umr3523,paris, France, institut pasteur,unité de génomique virale et vaccination,paris,france,cnrs,umr3569,paris,france,mcgill university,department of human genetics,centre for the study of host resistance,montreal,qc, Canada, institut pasteur,unité de génomique virale et vaccination,paris,france,cnrs,umr3569,paris, France, institut pasteur,unité de biochimie structurale,paris,france,cnrs,umr 3528,paris,france,inra,unité mathémathique,informatique et génome,jouy-en-josas, France, institut pasteur,unité de génomique virale et vaccination,paris,france,cnrs,umr3569,paris, France, institut pasteur,unité de génomique virale et vaccination,paris,france,cnrs,umr3569,paris, France, institut pasteur,unité interactions moléculaires flavivirus-hôtes,paris, France, cnrs,umr3569,paris,france,institut pasteur,unité de génétique moléculaire des virus à arn,paris,france,dana-farber cancer institute,center for cancer systems biology (ccsb) and department of cancer biology,boston,ma, United States, institut pasteur,unité de chimie et biocatalyse,paris,france,cnrs,umr3523,paris, France, institut pasteur,unité de génomique virale et vaccination,paris,france,cnrs,umr3569,paris, France, institut pasteur,unité de génomique virale et vaccination,paris,france,cnrs,umr3569,paris, France
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Authors
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