Hepatitis C Virus (HCV) Evades NKG2D-Dependent NK Cell Responses through NS5A-Mediated Imbalance of Inflammatory Cytokines

PLoS Pathogens

Patrice Cacoub¹  Michal Abel²  Patrice N. Marche³  Marion Lambert⁴  Arielle R. Rosenberg⁴  Damien Sène⁴  Céline Hernandez⁴  Sophie Caillat-Zucman⁵  Franck Levasseur⁶  Véronique Pène⁶  Evelyne Jouvin-Marche⁶  Xavier Camous⁶ 

[1] Université Joseph Fourier-Grenoble I, Faculté de Médecine, Institut Albert Bonniot, UMR-S823, Grenoble, France;AP-HP, Hôpital Pitié-Salpêtrière, Département de Médecine Interne, Paris, France;INSERM, U823;Institut National de la Santé et de la Recherche Médicale (INSERM), U986, Hôpital St-Vincent de Paul, Paris, France;Université Paris Descartes, EA 4474 “Hepatitis C Virology”, Paris, France;Université Paris Descartes, Faculté de Médecine, Paris, France

关键词: NK cells;    Monocytes;    Hepatitis C virus;    Flow cytometry;    Toll-like receptors;    Enzyme-linked immunoassays;    Recombinant proteins;    Immune receptor signaling;   

DOI  :  10.1371/journal.ppat.1001184

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY