研究揭示了肝脏对乙型肝炎病毒复制的“弱点”

StephenW

Study reveals the liver's 'weak spot' for hepatitis B virus replication
February 13, 2018, Agency for Science, Technology and Research (A*STAR), Singapore
Study reveals the liver’s ‘weak spot’ for hepatitis B virus replication
In the absence of protective proteins Slug and SOX7, hepatitis B infection thrives in liver cells, indicated by green staining in this image. Credit: A*STAR Singapore Immunology Network

In a surprising discovery, researchers from the Singapore Immunology Network (SIgN), A*STAR, have found that the liver is the main site of hepatitis B (HBV) replication—not only because it contains material that helps the virus proliferate, but also because most other tissues of the body contain proteins that actively repress HBV replication.

"We've been working on this project for a number of years because HBV is very prevalent in Asia," says Ee Chee Ren, leader of the SIgN team that made the discovery.

"HBV enters the liver cells through specific receptors and then deposits its genetic material into the nucleus," explains SIgN's Hui Ling Ko, the paper's first author. The viral DNA then hijacks the host cell's machinery to make new copies of HBV. While it's known that liver cells contain factors that facilitate HBV replication, Ko and her team found that the cells also lack functional levels of the proteins Slug and SOX7. These proteins are found in most other human tissues, where they bind to the HBV genome and block the binding of the cells' proteins that initiate and promote viral replication. "Slug and SOX7 are involved in embryonic development and that's when they're most active," says Ko. After development, it is thought that the proteins are no longer required in the liver, and so get 'turned off.'

The team is now using tools including CRISPR-Cas9, the pioneering gene editing technology, to produce cells without any functioning Slug or SOX7 proteins. This nullifies the cells' defenses against HBV infection so that they can be used to test the efficacy of new drugs. "The reason for the very successful development of antiviral drugs for hepatitis C was the availability of robust, cell-based screening assays. Hepatitis B has always been lacking in this area," says Ren. "When we introduce HBV into these Slug-deficient cell lines, they show a large increase in the viral load. This provides us with a dramatically improved platform to create a drug screening assay for HBV."

The SIgN team made another unexpected discovery during their studies: human colon, lung and stomach cells also lack Slug and SOX7. The scientists are now collaborating with clinicians at Singapore General Hospital to launch a thorough investigation into whether these tissues could act as a hidden reservoir of HBV, potentially complicating disease treatment.

Explore further: Hepatitis therapy: Kupffer cells adjust the balance between pathogen control and hepatocyte regenera

More information: Hui Ling Ko et al. Identification of Slug and SOX7 as transcriptional repressors binding to the hepatitis B virus core promoter, Journal of Hepatology (2017). DOI: 10.1016/j.jhep.2017.08.033

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StephenW

研究揭示了肝脏对乙型肝炎病毒复制的“弱点”
2018年2月13日，新加坡科学技术与研究局（A * STAR）
研究揭示了肝脏对乙型肝炎病毒复制的“弱点”
在没有保护性蛋白Slug和SOX7的情况下，乙肝感染在肝细胞中繁殖，这种图像中的绿色染色表明。信用：A * STAR新加坡免疫学网络

一项令人惊讶的发现是，新加坡免疫学网络（SIgN）的研究人员A * STAR发现肝脏是乙型肝炎病毒复制的主要部位 - 不仅因为它含有帮助病毒增殖的物质，而且还因为身体的其他大部分组织都含有积极抑制HBV复制的蛋白质。

“我们一直在研究这个项目多年，因为HBV在亚洲非常流行，”发现的SIgN团队领导Ee Chee Ren说。

“HBV通过特定的受体进入肝细胞，然后将其遗传物质沉积到细胞核中”，该论文的第一作者SIgN的Hui Ling Ko解释说。然后病毒DNA劫持宿主细胞的机器来制造新的HBV拷贝。虽然已知肝细胞含有促进HBV复制的因子，但Ko和她的研究小组发现该细胞也缺乏功能水平的Slug和SOX7蛋白。这些蛋白质在大多数其他人体组织中发现，在那里它们与HBV基因组结合并阻断启动和促进病毒复制的细胞蛋白质的结合。 Ko说：“Slug和SOX7参与胚胎发育，这是他们最活跃的时期。发育后，人们认为肝脏中不再需要蛋白质，因此“关闭”。

该团队现在使用的工具包括开创性的基因编辑技术CRISPR-Cas9来生产没有任何功能Slug或SOX7蛋白的细胞。这使细胞对抗HBV感染的抵抗力下降，从而可以用它们来测试新药的功效。 “丙型肝炎抗病毒药物的成功开发的原因在于可用强大的基于细胞的筛选试验，在该领域一直缺乏乙型肝炎，”Ren说。 “当我们将HBV引入这些Slug缺陷型细胞系时，它们表现出病毒载量的大幅增加，这为我们提供了一个显着改进的平台，用于创建HBV的药物筛选测定。”

SIgN团队在研究期间发现了另一个意外发现：人类结肠，肺和胃细胞也缺乏Slug和SOX7。科学家现在正与新加坡中央医院的临床医生合作，对这些组织是否可以充当隐藏的HBV储库进行彻底调查，可能使疾病治疗复杂化。

进一步探索：肝炎治疗：枯否细胞调节病原体控制和肝细胞再生之间的平衡

更多信息：Hui Ling Ko et al。鉴定Slug和SOX7作为与乙型肝炎病毒核心启动子结合的转录阻遏物，Journal of Hepatology（2017）。 DOI：10.1016 / j.jhep.2017.08.033

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