Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines.
Understanding how hepatitis C virus (HCV) induces and circumvents the host's natural killer (NK) cell-mediated immunity is of critical importance in efforts to design effective therapeutics. We report here the decreased expression of the NKG2D activating receptor as a novel strategy adopted by...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-11-01
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| Series: | PLoS Pathogens |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21085608/?tool=EBI |
| _version_ | 1818968800646660096 |
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| author | Damien Sène Franck Levasseur Michal Abel Marion Lambert Xavier Camous Céline Hernandez Véronique Pène Arielle R Rosenberg Evelyne Jouvin-Marche Patrice N Marche Patrice Cacoub Sophie Caillat-Zucman |
| author_facet | Damien Sène Franck Levasseur Michal Abel Marion Lambert Xavier Camous Céline Hernandez Véronique Pène Arielle R Rosenberg Evelyne Jouvin-Marche Patrice N Marche Patrice Cacoub Sophie Caillat-Zucman |
| author_sort | Damien Sène |
| collection | DOAJ |
| description | Understanding how hepatitis C virus (HCV) induces and circumvents the host's natural killer (NK) cell-mediated immunity is of critical importance in efforts to design effective therapeutics. We report here the decreased expression of the NKG2D activating receptor as a novel strategy adopted by HCV to evade NK-cell mediated responses. We show that chronic HCV infection is associated with expression of ligands for NKG2D, the MHC class I-related Chain (MIC) molecules, on hepatocytes. However, NKG2D expression is downmodulated on circulating NK cells, and consequently NK cell-mediated cytotoxic capacity and interferon-γ production are impaired. Using an endotoxin-free recombinant NS5A protein, we show that NS5A stimulation of monocytes through Toll-like Receptor 4 (TLR4) promotes p38- and PI3 kinase-dependent IL-10 production, while inhibiting IL-12 production. In turn, IL-10 triggers secretion of TGFβ which downmodulates NKG2D expression on NK cells, leading to their impaired effector functions. Moreover, culture supernatants of HCV JFH1 replicating Huh-7.5.1 cells reproduce the effect of recombinant NS5A on NKG2D downmodulation. Exogenous IL-15 can antagonize the TGFβ effect and restore normal NKG2D expression on NK cells. We conclude that NKG2D-dependent NK cell functions are modulated during chronic HCV infection, and demonstrate that this alteration can be prevented by exogenous IL-15, which could represent a meaningful adjuvant for therapeutic intervention. |
| first_indexed | 2024-12-20T14:10:27Z |
| format | Article |
| id | doaj.art-7d4b8c71da6d4f89bb063c44cd7e01d1 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-20T14:10:27Z |
| publishDate | 2010-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-7d4b8c71da6d4f89bb063c44cd7e01d12022-12-21T19:38:10ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742010-11-01611e100118410.1371/journal.ppat.1001184Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines.Damien SèneFranck LevasseurMichal AbelMarion LambertXavier CamousCéline HernandezVéronique PèneArielle R RosenbergEvelyne Jouvin-MarchePatrice N MarchePatrice CacoubSophie Caillat-ZucmanUnderstanding how hepatitis C virus (HCV) induces and circumvents the host's natural killer (NK) cell-mediated immunity is of critical importance in efforts to design effective therapeutics. We report here the decreased expression of the NKG2D activating receptor as a novel strategy adopted by HCV to evade NK-cell mediated responses. We show that chronic HCV infection is associated with expression of ligands for NKG2D, the MHC class I-related Chain (MIC) molecules, on hepatocytes. However, NKG2D expression is downmodulated on circulating NK cells, and consequently NK cell-mediated cytotoxic capacity and interferon-γ production are impaired. Using an endotoxin-free recombinant NS5A protein, we show that NS5A stimulation of monocytes through Toll-like Receptor 4 (TLR4) promotes p38- and PI3 kinase-dependent IL-10 production, while inhibiting IL-12 production. In turn, IL-10 triggers secretion of TGFβ which downmodulates NKG2D expression on NK cells, leading to their impaired effector functions. Moreover, culture supernatants of HCV JFH1 replicating Huh-7.5.1 cells reproduce the effect of recombinant NS5A on NKG2D downmodulation. Exogenous IL-15 can antagonize the TGFβ effect and restore normal NKG2D expression on NK cells. We conclude that NKG2D-dependent NK cell functions are modulated during chronic HCV infection, and demonstrate that this alteration can be prevented by exogenous IL-15, which could represent a meaningful adjuvant for therapeutic intervention.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21085608/?tool=EBI |
| spellingShingle | Damien Sène Franck Levasseur Michal Abel Marion Lambert Xavier Camous Céline Hernandez Véronique Pène Arielle R Rosenberg Evelyne Jouvin-Marche Patrice N Marche Patrice Cacoub Sophie Caillat-Zucman Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. PLoS Pathogens |
| title | Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. |
| title_full | Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. |
| title_fullStr | Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. |
| title_full_unstemmed | Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. |
| title_short | Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. |
| title_sort | hepatitis c virus hcv evades nkg2d dependent nk cell responses through ns5a mediated imbalance of inflammatory cytokines |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21085608/?tool=EBI |
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