乙型肝炎病毒感染的细胞分泌的细胞外囊泡在水动力乙肝病

StephenW

Extracellular Vesicles Secreted by HBV-infected Cells Modulate HBV Persistence in Hydrodynamic HBV Transfection Mouse Model
Masatoshi Kakizaki  1 , Yuichiro Yamamoto  1 , Motoyuki Otsuka  2 , Kouichi Kitamura  3 , Masatoshi Ito  1 , Hideki Derek Kawai  4 , Masamichi Muramatsu  3 , Tatehiro Kagawa  1 , Ai Kotani  1
Affiliations
Affiliations

    1
    Tokai University, Japan.
    2
    University of Tokyo, Japan.
    3
    National Institute of Infectious Diseases, Japan.
    4
    Soka University, Japan.

    PMID: 32651230 DOI: 10.1074/jbc.RA120.014317

Abstract

Hepatitis B, a viral infection that affects the liver, is thought to affect over 257 million people worldwide, and long-term infection can lead to life-threatening issues such as cirrhosis or liver cancer. Chronic hepatitis B develops by the interaction between Hepatitis B virus (HBV) and host immune response. However, questions of how HBV-infected cells thwart immune system defenses remain unanswered. Extracellular vesicles (EVs) are used for cellular communication, carrying cargoes such as RNAs, proteins and lipids and delivering them intracellularly after being endocytosed by target cells. HBV-infected liver cells secrete several types of EVs into body fluids such as complete and incomplete virions, and exosomes. We previously demonstrated that monocytes that incorporated EVs moved to immunoregulatory phenotypes via upregulation of PD-L1, an immunocheckpoint molecule, and downregulation of CD69, a leukocyte activation molecule. In this study, we transfected mice with HBV using hydrodynamic injection and studied the effects of EVs secreted by HBV-infected liver cells. EVs secreted from cells with HBV replication strongly suppressed the immune response, inhibiting the eradication of HBV-replicating cells in the mice transfected with HBV. EVs were systemically incorporated in multiple organs, including liver, bone marrow (BM) and intestine. Intriguingly, the BM cells which incorporated EVs acquired intestinal tropism and the dendritic cell populations in the intestine increased. These findings suggest that the EVs secreted by HBV-infected liver cells exert immunosuppressive functions, and that an association between the liver, bone marrow and intestinal tract exists through EVs secreted from HBV-infected cells.

Keywords: PD-L1; dendritic cell; extracellular vesicles; hepatitis B virus (HBV, Hep B); hydrodynamic HBV transfection mouse model; immunosuppression; viral immunology.

Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

StephenW

乙型肝炎病毒感染的细胞分泌的细胞外囊泡在水动力乙肝病毒转染小鼠模型中调节乙肝病毒的持久性。
柿崎正敏1，山本雄一郎1，大冢元之2，北村幸一3，伊藤正敏1，河井秀树4，村松正敏3，香川立宏1，小谷爱1
隶属关系
隶属关系

    1个
    日本东海大学。
    2
    日本东京大学。
    3
    日本国立传染病研究所。
    4
    日本创价大学。

    PMID：32651230 DOI：10.1074 / jbc.RA120.014317

抽象

乙型肝炎是一种影响肝脏的病毒感染，被认为影响了全球超过2.57亿人，长期感染会导致威胁生命的问题，例如肝硬化或肝癌。慢性乙型肝炎是通过乙型肝炎病毒（HBV）和宿主免疫反应之间的相互作用发展而来的。然而，关于HBV感染的细胞如何阻碍免疫系统防御的问题仍未得到解答。细胞外囊泡（EVs）用于细胞通讯，运载诸如RNA，蛋白质和脂质等货物，并在被靶细胞内吞后在细胞内传递。感染了HBV的肝细胞会将几种类型的EV分泌到体液中，例如完整和不完整的病毒颗粒以及外泌体。我们先前证明，结合了EV的单核细胞通过上调PD-L1（一种免疫检查点分子）和下调CD69（一种白细胞激活分子）而转变为免疫调节表型。在这项研究中，我们使用水动力注射转染了HBV小鼠，并研究了被HBV感染的肝细胞分泌的EV的作用。具有HBV复制功能的细胞分泌的EV强烈抑制了免疫反应，从而抑制了转染HBV的小鼠中HBV复制细胞的清除。电动汽车被系统地整合到多个器官中，包括肝脏，骨髓（BM）和肠道。有趣的是，结合了EV的BM细胞获得了肠道嗜性，并且肠道中的树突状细胞数量增加。这些发现表明，由HBV感染的肝细胞分泌的EV具有免疫抑制功能，并且通过由HBV感染的细胞分泌的EV存在肝，骨髓和肠道之间的联系。

关键字：PD-L1;树突状细胞细胞外囊泡;乙型肝炎病毒（HBV，乙肝）；流体动力学HBV转染小鼠模型；免疫抑制病毒免疫学。

经美国生物化学和分子生物学学会许可发行。

StephenW

https://www.jbc.org/content/earl ... 120.014317.full.pdf