Transmitted/Founder Hepatitis C Viruses Induce Cell-Type- and Genotype-Specific Differences in Innate Signaling within the Liver

ABSTRACT Hepatitis C virus (HCV) infection leads to persistence in the majority of cases despite triggering complex innate immune responses within the liver. Although hepatocytes are the preferred site for HCV replication, nonparenchymal cells (NPCs) can also contribute to antiviral immunity. Recent...

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Autores principales:	Angela M. Mitchell, Amy E. L. Stone, Linling Cheng, Kimberly Ballinger, Michael G. Edwards, Mark Stoddard, Hui Li, Lucy Golden-Mason, George M. Shaw, Salman Khetani, Hugo R. Rosen
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bb2504d3a0534ff6a5d2521177419f69
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spelling	oai:doaj.org-article:bb2504d3a0534ff6a5d2521177419f692021-11-15T15:41:33ZTransmitted/Founder Hepatitis C Viruses Induce Cell-Type- and Genotype-Specific Differences in Innate Signaling within the Liver10.1128/mBio.02510-142150-7511https://doaj.org/article/bb2504d3a0534ff6a5d2521177419f692015-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02510-14https://doaj.org/toc/2150-7511ABSTRACT Hepatitis C virus (HCV) infection leads to persistence in the majority of cases despite triggering complex innate immune responses within the liver. Although hepatocytes are the preferred site for HCV replication, nonparenchymal cells (NPCs) can also contribute to antiviral immunity. Recent innovations involving single-genome amplification (SGA), direct amplicon sequencing, and phylogenetic inference have identified full-length transmitted/founder (T/F) viruses. Here, we tested the effect of HCV T/F viral RNA (vRNA) on innate immune signaling within hepatocytes and NPCs, including the HepG2 and Huh 7.5.1 cell lines, a human liver endothelial cell line (TMNK-1), a plasmacytoid dendritic cell line (GEN2.2), and a monocytic cell line (THP-1). Transfection with hepatitis C T/F vRNA induced robust transcriptional upregulation of type I and III interferons (IFNs) within HepG2 and TMNK-1 cells. Both the THP-1 and GEN2.2 lines demonstrated higher type I and III IFN transcription with genotype 3a compared to genotype 1a or 1b. Supernatants from HCV T/F vRNA-transfected TMNK-1 cells demonstrated superior viral control. Primary human hepatocytes (PHH) transfected with genotype 3a induced canonical pathways that included chemokine and IFN genes, as well as overrepresentation of RIG-I (DDX58), STAT1, and a Toll-like receptor 3 (TLR3) network. Full-length molecular clones of HCV induce broad IFN responses within hepatocytes and NPCs, highlighting that signals imparted by the various cell types within the liver may lead to divergent outcomes of infection. In particular, the finding that HCV genotypes differentially induce antiviral responses in NPCs and PHH might account for relevant clinical-epidemiological observations (higher clearance but greater necroinflammation in persistence with genotype 3). IMPORTANCE Hepatitis C virus (HCV) has become a major worldwide problem, and it is now the most common viral infection for which there is no vaccine. HCV infection often leads to persistence of the virus and is a leading cause of chronic hepatitis, liver cancer, and cirrhosis. There are multiple genotypes of the virus, and patients infected with different viral genotypes respond to traditional therapy differently. However, the immune response to the virus within the liver has not been fully elucidated. Here, we determined the responses to different genotypes of HCV in cell types of the liver. We found that the immune response varied according to both cell type and HCV genotype, leading to a more pronounced induction of inflammatory pathways after exposure to certain genotypes. Therefore, inflammatory pathways that are being robustly activated by certain HCV genotypes could lead to more severe damage to the liver, inducing diverse outcomes and responses to therapy.Angela M. MitchellAmy E. L. StoneLinling ChengKimberly BallingerMichael G. EdwardsMark StoddardHui LiLucy Golden-MasonGeorge M. ShawSalman KhetaniHugo R. RosenAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 2 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Angela M. Mitchell Amy E. L. Stone Linling Cheng Kimberly Ballinger Michael G. Edwards Mark Stoddard Hui Li Lucy Golden-Mason George M. Shaw Salman Khetani Hugo R. Rosen Transmitted/Founder Hepatitis C Viruses Induce Cell-Type- and Genotype-Specific Differences in Innate Signaling within the Liver
description	ABSTRACT Hepatitis C virus (HCV) infection leads to persistence in the majority of cases despite triggering complex innate immune responses within the liver. Although hepatocytes are the preferred site for HCV replication, nonparenchymal cells (NPCs) can also contribute to antiviral immunity. Recent innovations involving single-genome amplification (SGA), direct amplicon sequencing, and phylogenetic inference have identified full-length transmitted/founder (T/F) viruses. Here, we tested the effect of HCV T/F viral RNA (vRNA) on innate immune signaling within hepatocytes and NPCs, including the HepG2 and Huh 7.5.1 cell lines, a human liver endothelial cell line (TMNK-1), a plasmacytoid dendritic cell line (GEN2.2), and a monocytic cell line (THP-1). Transfection with hepatitis C T/F vRNA induced robust transcriptional upregulation of type I and III interferons (IFNs) within HepG2 and TMNK-1 cells. Both the THP-1 and GEN2.2 lines demonstrated higher type I and III IFN transcription with genotype 3a compared to genotype 1a or 1b. Supernatants from HCV T/F vRNA-transfected TMNK-1 cells demonstrated superior viral control. Primary human hepatocytes (PHH) transfected with genotype 3a induced canonical pathways that included chemokine and IFN genes, as well as overrepresentation of RIG-I (DDX58), STAT1, and a Toll-like receptor 3 (TLR3) network. Full-length molecular clones of HCV induce broad IFN responses within hepatocytes and NPCs, highlighting that signals imparted by the various cell types within the liver may lead to divergent outcomes of infection. In particular, the finding that HCV genotypes differentially induce antiviral responses in NPCs and PHH might account for relevant clinical-epidemiological observations (higher clearance but greater necroinflammation in persistence with genotype 3). IMPORTANCE Hepatitis C virus (HCV) has become a major worldwide problem, and it is now the most common viral infection for which there is no vaccine. HCV infection often leads to persistence of the virus and is a leading cause of chronic hepatitis, liver cancer, and cirrhosis. There are multiple genotypes of the virus, and patients infected with different viral genotypes respond to traditional therapy differently. However, the immune response to the virus within the liver has not been fully elucidated. Here, we determined the responses to different genotypes of HCV in cell types of the liver. We found that the immune response varied according to both cell type and HCV genotype, leading to a more pronounced induction of inflammatory pathways after exposure to certain genotypes. Therefore, inflammatory pathways that are being robustly activated by certain HCV genotypes could lead to more severe damage to the liver, inducing diverse outcomes and responses to therapy.
format	article
author	Angela M. Mitchell Amy E. L. Stone Linling Cheng Kimberly Ballinger Michael G. Edwards Mark Stoddard Hui Li Lucy Golden-Mason George M. Shaw Salman Khetani Hugo R. Rosen
author_facet	Angela M. Mitchell Amy E. L. Stone Linling Cheng Kimberly Ballinger Michael G. Edwards Mark Stoddard Hui Li Lucy Golden-Mason George M. Shaw Salman Khetani Hugo R. Rosen
author_sort	Angela M. Mitchell
title	Transmitted/Founder Hepatitis C Viruses Induce Cell-Type- and Genotype-Specific Differences in Innate Signaling within the Liver
title_short	Transmitted/Founder Hepatitis C Viruses Induce Cell-Type- and Genotype-Specific Differences in Innate Signaling within the Liver
title_full	Transmitted/Founder Hepatitis C Viruses Induce Cell-Type- and Genotype-Specific Differences in Innate Signaling within the Liver
title_fullStr	Transmitted/Founder Hepatitis C Viruses Induce Cell-Type- and Genotype-Specific Differences in Innate Signaling within the Liver
title_full_unstemmed	Transmitted/Founder Hepatitis C Viruses Induce Cell-Type- and Genotype-Specific Differences in Innate Signaling within the Liver
title_sort	transmitted/founder hepatitis c viruses induce cell-type- and genotype-specific differences in innate signaling within the liver
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/bb2504d3a0534ff6a5d2521177419f69
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Transmitted/Founder Hepatitis C Viruses Induce Cell-Type- and Genotype-Specific Differences in Innate Signaling within the Liver

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