title: Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection.
abstract: The innate immune system is essential for controlling viral infection. Hepatitis B virus (HBV) persistently infects human hepatocytes and causes hepatocellular carcinoma. However, the innate immune response to HBV infection in vivo remains unclear. Using a tree shrew animal model, we showed that HBV infection induced hepatic interferon (IFN)-γ expression during early infection. Our in vitro study demonstrated that hepatic NK cells produced IFN-γ in response to HBV only in the presence of hepatic F4/80(+) cells. Moreover, extracellular vesicles (EVs) released from HBV-infected hepatocytes contained viral nucleic acids and induced NKG2D ligand expression in macrophages by stimulating MyD88, TICAM-1, and MAVS-dependent pathways. In addition, depletion of exosomes from EVs markedly reduced NKG2D ligand expression, suggesting the importance of exosomes for NK cell activation. In contrast, infection of hepatocytes with HBV increased immunoregulatory microRNA levels in EVs and exosomes, which were transferred to macrophages, thereby suppressing IL-12p35 mRNA expression in macrophages to counteract the host innate immune response. IFN-γ increased the hepatic expression of DDX60 and augmented the DDX60-dependent degradation of cytoplasmic HBV RNA. Our results elucidated the crucial role of exosomes in antiviral innate immune response against HBV.
  Accession number of RNA-seq data is DRA004164 (DRA in DDBJ).
authors.affiliation: Department of Immunology, Graduate School of Medical Sciences, Kumamoto University , Honjo, Chuo-ku, Kumamoto , Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kouwaki
authors.affiliation: Department of Immunology, Graduate School of Medical Sciences, Kumamoto University , Honjo, Chuo-ku, Kumamoto , Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Fukushima
authors.affiliation: Laboratory for Biologics Development, Research Center for Zoonosis Control, GI-CoRE Global Station for Zoonosis Control, Hokkaido University , Kita-Ku, Sapporo , Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Daito
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science , Kamikitazawa, Setagaya-ku, Tokyo , Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sanada
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science , Kamikitazawa, Setagaya-ku, Tokyo , Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Laboratory for Biologics Development, Research Center for Zoonosis Control, GI-CoRE Global Station for Zoonosis Control, Hokkaido University , Kita-Ku, Sapporo , Japan.
authors.forename: Edin J
authors.initials: EJ
authors.lastname: Mifsud
authors.affiliation: Section of Bioengineering Technology, Universiti Kuala Lumpur (UniKL) MICET , Melaka , Malaysia.
authors.forename: Chean Ring
authors.initials: CR
authors.lastname: Leong
authors.affiliation: Joint Faculty of Veterinary Medicine, Transboundary Animal Diseases Center, Kagoshima University , Korimoto, Kagoshima , Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tsukiyama-Kohara
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science , Kamikitazawa, Setagaya-ku, Tokyo , Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Kohara
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University , Kita-Ku, Sapporo , Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University , Kita-Ku, Sapporo , Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
authors.affiliation: Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Honjo, Chuo-ku, Kumamoto, Japan; Laboratory for Biologics Development, Research Center for Zoonosis Control, GI-CoRE Global Station for Zoonosis Control, Hokkaido University, Kita-Ku, Sapporo, Japan; Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita-Ku, Sapporo, Japan; JST, PREST, Honjo, Chuo-ku, Kumamoto, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Oshiumi
keywords: exosome; innate immunity; virus