IRF3-mediated pathogenicity in a murine model of human hepatitis A.

HAV-infected Ifnar1-/- mice recapitulate many of the cardinal features of hepatitis A in humans, including serum alanine aminotransferase (ALT) elevation, hepatocellular apoptosis, and liver inflammation. Previous studies implicate MAVS-IRF3 signaling in pathogenesis, but leave unresolved the role o...

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Autores principales:	Lu Sun, You Li, Ichiro Misumi, Olga González-López, Lucinda Hensley, John M Cullen, David R McGivern, Mami Matsuda, Ryosuke Suzuki, Ganes C Sen, Asuka Hirai-Yuki, Jason K Whitmire, Stanley M Lemon
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b97fa5a3c6024389911f79c898d10f9e
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spelling	oai:doaj.org-article:b97fa5a3c6024389911f79c898d10f9e2021-12-02T20:00:05ZIRF3-mediated pathogenicity in a murine model of human hepatitis A.1553-73661553-737410.1371/journal.ppat.1009960https://doaj.org/article/b97fa5a3c6024389911f79c898d10f9e2021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009960https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374HAV-infected Ifnar1-/- mice recapitulate many of the cardinal features of hepatitis A in humans, including serum alanine aminotransferase (ALT) elevation, hepatocellular apoptosis, and liver inflammation. Previous studies implicate MAVS-IRF3 signaling in pathogenesis, but leave unresolved the role of IRF3-mediated transcription versus the non-transcriptional, pro-apoptotic activity of ubiquitylated IRF3. Here, we compare the intrahepatic transcriptomes of infected versus naïve Mavs-/- and Ifnar1-/- mice using high-throughput sequencing, and identify IRF3-mediated transcriptional responses associated with hepatocyte apoptosis and liver inflammation. Infection was transcriptionally silent in Mavs-/- mice, in which HAV replicates robustly within the liver without inducing inflammation or hepatocellular apoptosis. By contrast, infection resulted in the upregulation of hundreds of genes in Ifnar1-/- mice that develop acute hepatitis closely modeling human disease. Upregulated genes included pattern recognition receptors, interferons, chemokines, cytokines and other interferon-stimulated genes. Compared with Ifnar1-/- mice, HAV-induced inflammation was markedly attenuated and there were few apoptotic hepatocytes in livers of infected Irf3S1/S1Ifnar1-/- mice in which IRF3 is transcriptionally-inactive due to alanine substitutions at Ser-388 and Ser-390. Although transcriptome profiling revealed remarkably similar sets of genes induced in Irf3S1/S1Ifnar1-/- and Ifnar1-/- mice, a subset of genes was differentially expressed in relation to the severity of the liver injury. Prominent among these were both type 1 and type III interferons and interferon-responsive genes associated previously with apoptosis, including multiple members of the ISG12 and 2'-5' oligoadenylate synthetase families. Ifnl3 and Ifnl2 transcript abundance correlated strongly with disease severity, but mice with dual type 1 and type III interferon receptor deficiency remained fully susceptible to liver injury. Collectively, our data show that IRF3-mediated transcription is required for HAV-induced liver injury in mice and identify key IRF3-responsive genes associated with pathogenicity, providing a clear distinction from the transcription-independent role of IRF3 in liver injury following binge exposure to alcohol.Lu SunYou LiIchiro MisumiOlga González-LópezLucinda HensleyJohn M CullenDavid R McGivernMami MatsudaRyosuke SuzukiGanes C SenAsuka Hirai-YukiJason K WhitmireStanley M LemonPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 9, p e1009960 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Lu Sun You Li Ichiro Misumi Olga González-López Lucinda Hensley John M Cullen David R McGivern Mami Matsuda Ryosuke Suzuki Ganes C Sen Asuka Hirai-Yuki Jason K Whitmire Stanley M Lemon IRF3-mediated pathogenicity in a murine model of human hepatitis A.
description	HAV-infected Ifnar1-/- mice recapitulate many of the cardinal features of hepatitis A in humans, including serum alanine aminotransferase (ALT) elevation, hepatocellular apoptosis, and liver inflammation. Previous studies implicate MAVS-IRF3 signaling in pathogenesis, but leave unresolved the role of IRF3-mediated transcription versus the non-transcriptional, pro-apoptotic activity of ubiquitylated IRF3. Here, we compare the intrahepatic transcriptomes of infected versus naïve Mavs-/- and Ifnar1-/- mice using high-throughput sequencing, and identify IRF3-mediated transcriptional responses associated with hepatocyte apoptosis and liver inflammation. Infection was transcriptionally silent in Mavs-/- mice, in which HAV replicates robustly within the liver without inducing inflammation or hepatocellular apoptosis. By contrast, infection resulted in the upregulation of hundreds of genes in Ifnar1-/- mice that develop acute hepatitis closely modeling human disease. Upregulated genes included pattern recognition receptors, interferons, chemokines, cytokines and other interferon-stimulated genes. Compared with Ifnar1-/- mice, HAV-induced inflammation was markedly attenuated and there were few apoptotic hepatocytes in livers of infected Irf3S1/S1Ifnar1-/- mice in which IRF3 is transcriptionally-inactive due to alanine substitutions at Ser-388 and Ser-390. Although transcriptome profiling revealed remarkably similar sets of genes induced in Irf3S1/S1Ifnar1-/- and Ifnar1-/- mice, a subset of genes was differentially expressed in relation to the severity of the liver injury. Prominent among these were both type 1 and type III interferons and interferon-responsive genes associated previously with apoptosis, including multiple members of the ISG12 and 2'-5' oligoadenylate synthetase families. Ifnl3 and Ifnl2 transcript abundance correlated strongly with disease severity, but mice with dual type 1 and type III interferon receptor deficiency remained fully susceptible to liver injury. Collectively, our data show that IRF3-mediated transcription is required for HAV-induced liver injury in mice and identify key IRF3-responsive genes associated with pathogenicity, providing a clear distinction from the transcription-independent role of IRF3 in liver injury following binge exposure to alcohol.
format	article
author	Lu Sun You Li Ichiro Misumi Olga González-López Lucinda Hensley John M Cullen David R McGivern Mami Matsuda Ryosuke Suzuki Ganes C Sen Asuka Hirai-Yuki Jason K Whitmire Stanley M Lemon
author_facet	Lu Sun You Li Ichiro Misumi Olga González-López Lucinda Hensley John M Cullen David R McGivern Mami Matsuda Ryosuke Suzuki Ganes C Sen Asuka Hirai-Yuki Jason K Whitmire Stanley M Lemon
author_sort	Lu Sun
title	IRF3-mediated pathogenicity in a murine model of human hepatitis A.
title_short	IRF3-mediated pathogenicity in a murine model of human hepatitis A.
title_full	IRF3-mediated pathogenicity in a murine model of human hepatitis A.
title_fullStr	IRF3-mediated pathogenicity in a murine model of human hepatitis A.
title_full_unstemmed	IRF3-mediated pathogenicity in a murine model of human hepatitis A.
title_sort	irf3-mediated pathogenicity in a murine model of human hepatitis a.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/b97fa5a3c6024389911f79c898d10f9e
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IRF3-mediated pathogenicity in a murine model of human hepatitis A.

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