title: Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction.
abstract: Evidence suggests that exosomes can transfer genetic material between cells. However, their roles in hepatitis B virus (HBV) infection remain unclear. Here, we report that exosomes present in the sera of chronic hepatitis B (CHB) patients contained both HBV nucleic acids and HBV proteins, and transferred HBV to hepatocytes in an active manner. Notably, HBV nucleic acids were detected in natural killer (NK) cells from both CHB patients and healthy donors after exposure to HBV-positive exosomes. Through real-time fluorescence microscopy and flow cytometry, 1,1'-dioctadecyl-3,3,3',3',-tetramethylindodicarbocyanine, 4-chlorobenzenesulfnate salt (DiD)-labeled exosomes were observed to interact with NK cells and to be taken up by NK cells, which was enhanced by transforming growth factor-β treatment. Furthermore, HBV-positive exosomes impaired NK-cell functions, including interferon (IFN)-γ production, cytolytic activity, NK-cell proliferation and survival, as well as the responsiveness of the cells to poly (I:C) stimulation. HBV infection suppressed the expression of pattern-recognition receptors, especially retinoic acid inducible gene I (RIG-I), on NK cells, resulting in the dampening of the nuclear factor κB(NF-κB) and p38 mitogen-activated protein kinase pathways. Our results highlight a previously unappreciated role of exosomes in HBV transmission and NK-cell dysfunction during CHB infection.
authors.affiliation: Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Yinli
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Han
authors.affiliation: Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Cai
authors.initials: C
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
authors.affiliation: Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000276:immunology / Q000821:virology; D016022:Case-Control Studies; D004279:DNA, Viral / Q000235:genetics; D055354:Exosomes / Q000821:virology*; D005260:Female; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000635:transmission* / Q000821:virology; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008113:Liver Neoplasms / Q000453:epidemiology / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004279:DNA, Viral; D016328:NF-kappa B; D048051:p38 Mitogen-Activated Protein Kinases