Elucidation of the stealth mechanism of infection chronicity by hepatitis B virus and drug discovery of inhibitory molecular targets

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K08937
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Tsubota Akihito 東京慈恵会医科大学, 医学部, 教授 (90322643)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: B型肝炎ウイルス / B型肝炎 / 肝炎慢性化 / microRNA / mRNA

Outline of Final Research Achievements

We generated an HBV-infected humanized liver chimera mouse model and performed transcriptome analysis of liver tissues. As a result, three miRNAs were persistently and highly up-regulated throughout the period from immediately after HBV infection, and a comprehensive gene profile suggested the stealth property of HBV.
When miRNAs were transfected into primary hepatocytes using lentiviral vectors, the amount of HBV in supernatant fluids/cells decreased in a dose-dependent manner. Conversely, it increased in a dose-dependent manner when those miRNA inhibitors were transfected as well. When siRNAs of target mRNAs specific to each miRNA confirmed by luciferase reporter assay were transfected into primary hepatocytes, the amount of HBV in supernatant fluids/cells showed an inversely correlated trend with the results of miRNA inhibitors. These results may help clarify the mechanism of HBV infection chronicity and drug discovery of inhibitory molecular targets.

Free Research Field

ウイルス性肝炎

Academic Significance and Societal Importance of the Research Achievements

B型肝炎は世界的に未だ主要な感染症であり、深刻な健康問題や経済的損失をもたらしている。特に感染の慢性化には急務な対応が必要である。肝炎が慢性化すれば、B型肝炎ウイルス（HBV）の特性上、感染肝細胞からの完全排除は困難だからである。これを克服するには、感染慢性化の機序解明と阻止が一つの戦略になる。
本研究で同定されたmicroRNA/mRNA分子がヒト肝細胞へのHBV感染効率や複製に影響を及ぼすことが明らかになった。これらの分子が免疫系に及ぼす影響やB型肝炎の慢性化阻止に向けた新たな分子標的としての有益性は今後の課題であるが、その一助になり得る研究成果と考えられ、将来的に社会還元が期待される。