戊型肝炎病毒Viroporin蛋白研究助力新疗法开发

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肝炎病毒一直是人类健康的大敌之一。在过去几十年中，人类在对抗甲肝、乙肝以及丙肝等多种肝炎过程中取得了极大成就。但是对于戊型肝炎目前尚没有一种对应的疗法被批准。而据世界卫生组织统计，每年全球有2000万人感染戊型肝炎病毒，这种病毒主要通过被污染的食物和水进行传播。这些患者绝大部分分布在东非和南非地区，而近年来欧洲感染这一病毒的患者数目也在不断增加，其中一个重要原因就是食用未经烹饪的肉类。因此，对于临床研究人员来说，开发戊肝疾病药物已经迫在眉睫。

最近，来自普林斯顿的研究人员在PNAS上发表了一份研究论文，报告了他们在病毒侵染细胞过程中的新发现，这一发现将有助于开发针对戊肝病毒的新疗法。在戊肝病毒侵染细胞周期中，一种名为Viroporin的蛋白在感染病毒的细胞释放成熟病毒过程中起到了重要作用。这种蛋白能够在细胞膜表面打孔，从而使已经组装成熟的新病毒释放出细胞，并进一步侵染其他健康细胞。

普林斯顿的研究人员发现，病毒RNA中的一个开放阅读框-3（ORF-3）在病毒在宿主细胞中合成Viroporin蛋白过程中起到关键作用。为了证明这一机制，研究人员利用非洲爪蟾细胞系构建出了一个模型并利用病毒侵染后测量模型的电阻值变化，结果发现ORF3 RNA在其中起到了类似“离子通道”的作用，并破坏了被侵染细胞细胞膜的生理功能，从而帮助成熟病毒释放。

下一步，研究人员将利用这一发现深入研究ORF3相关通路，并以此为靶点设计对应的药物分子用于治疗戊型肝炎。事实上，通过干扰病毒viroporin的合成来治疗疾病的思路此前已经被广泛用于包括HIV、丙肝在内多种病毒疾病的药物开发。

戊肝病毒在健康人群中表现的症状相当轻微。但是这种病毒对于免疫系统脆弱的人群以及孕妇有着额外风险。目前仅在中国有戊肝病毒疫苗上市。相信未来科学家们会在这一疾病领域取得突破性进展。

Hepatitis E is a liver virus that causes 20 million infections a year, mostly in East and South Asia, according to the World Health Organization (WHO). The virus is primarily spread through contaminated food and water, but lately it’s been on the rise in Europe, where it’s believed to be caused by the consumption of undercooked meat.

There is no therapy that specifically attacks the E strain of the virus, but now researchers led by Princeton have found a clue that could lead to a targeted treatment.

The research team discovered that when hepatitis E infects cells, it makes “viroporins,” or proteins that create holes in the cell membrane allowing the virus to escape and spread, according to a release from Princeton. Drugs that disrupt viroporin production have already been developed for other viruses, including HIV and hepatitis C.

The key to targeting viroporin production is to figure out how the virus is learning to make the destructive proteins. In the case of hepatitis E, the Princeton researchers found that a section of the virus’ RNA called open reading frame 3 (ORF3) contains the instructions it needs to make viroporins. The research was published in the Proceedings of the National Academy of Sciences.

To prove ORF3 is the key to producing an escape route for hepatitis E particles, the scientists worked with researchers at Rutgers New Jersey Medical School on a model using cells from the African clawed frog. By measuring electric currents, they discovered that ORF3 RNA acts as an “ion channel,” disrupting the cells’ physiology to the point where virus particles could slip through and infect other cells.

Hepatitis E produces only mild symptoms in healthy people, but it is dangerous for people with compromised immune systems and women in the late stages of pregnancy, according to WHO. A vaccine has been developed but is only available in China.

The next step for the Princeton-led team is to find points along the ORF3 pathway that might be able to be targeted with drugs.

"We are working on identifying parts of the protein that could possibly prevent the formation of the ion channel or prevent the flux of ions through the channel," said Alexander Ploss, a Princeton assistant professor of molecular biology and the senior author of the study, in the release.