Extracellular vesicles secreted by HBV-infected cells modulate HBV persistence in hydrodynamic HBV transfection mouse model
Extracellular vesicles secreted by HBV-infected cells modulate HBV persistence in hydrodynamic HBV transfection mouse model
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DOI：
10.1074/jbc.ra120.014317
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发表时间：
2020-08-28
影响因子：
4.8
通讯作者：
Kotani, Ai
中科院分区：
文献类型：
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作者：
Kakizaki, Masatoshi;Yamamoto, Yuichiro;Kotani, Ai
B型肝炎是一种影响肝脏的病毒感染，被认为影响全球超过2.57亿人，长期感染可导致危及生命的问题，如肝硬化或肝癌。慢性B型肝炎是由B型肝炎病毒（HBV）与宿主免疫反应相互作用而发生的。然而，HBV感染的细胞如何阻碍免疫系统防御的问题仍然没有答案。细胞外囊泡（EV）用于细胞通讯，携带诸如RNA、蛋白质和脂质的货物，并在被靶细胞内吞后将它们递送到细胞内。HBV感染的肝细胞分泌几种类型的EV进入体液，如完全和不完全病毒体和外泌体。我们先前证明，并入EV的单核细胞通过上调PD-L1（一种免疫检查点分子）和下调CD 69（一种白细胞活化分子）而转移到免疫调节表型。在这项研究中，我们使用流体动力学注射法将HBV转染小鼠，并研究了HBV感染的肝细胞分泌的EV的影响。从HBV复制细胞分泌的EV强烈抑制免疫应答，抑制HBV转染小鼠中HBV复制细胞的根除。EV全身性地并入多个器官，包括肝脏、骨髓（BM）和肠。有趣的是，合并EV的BM细胞获得了肠道向性，并且肠道中的树突状细胞群增加。这些发现表明，由HBV感染的肝细胞分泌的EV发挥免疫抑制功能，并且通过由HBV感染的细胞分泌的EV存在肝脏、骨髓和肠道之间的关联。
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 up-regulation of PD-L1, an immunocheckpoint molecule, and down-regulation 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 that 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.