MRC AMED - INTERFERON STIMULATED DEFENCES THAT TARGET HEPATITIS B VIRUS (HBV) AND HEPATITIS D VIRUS (HDV)

MRC AMED - 干扰素刺激针对乙型肝炎病毒 (HBV) 和丁型肝炎病毒 (HDV) 的防御

• 批准号: MR/T029188/1
• 负责人: Sam Wilson
• 金额: $ 9.72万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT029188%2F1
• 关键词: MRC; AMED; INTERFERON; STIMULATED; DEFENCES

Context: Chronic infection with hepatitis B virus (HBV) is a leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. Hepatitis D virus (HDV) can only complete its lifecycle in HBV-infected cells. Thus, HDV is only observed in HBV-infected individuals and this HBV and HDV coinfection worsens HBV-related pathogenesis. Although most people suppress HBV without any clinical intervention, around 10% of people will become chronically infected 'carriers' and the resulting disease burden is a major global health problem (causing ~0.9 million deaths every year). Type I interferons have become a standard treatment for chronic HBV infection. However, the response rate can be as low as 30%, and there is a need to better-understand why some individuals respond to IFN therapies and some do not.Aims: Interferons stimulate the upregulation of hundreds of genes and exactly how this suppresses HBV/HDV, and which IFN-stimulated genes (ISGs) determine the clinical outcome of interferon therapy, is largely unknown. We propose to identify and characterize the interferon-stimulated defences that underlie the ability of type I interferons to promote the suppression of HBV/HDV. Approach: To uncover the individual host genes that mediate the suppression of HBV and HDV, we will carry out screens that simultaneously measure the ability of hundreds of individual ISGs to inhibit HBV and HDV. Our research team consists of experts at propagating HBV and HDV (from the National Institute of Infectious Diseases (NIID), Tokyo, Japan) and specialists at conducting ISG screens (based at the MRC University of Glasgow Centre for Virus Research (CVR) in Glasgow, UK). This combined expertise should facilitate the rapid identification of genes that inhibit HBV and HDV. Following these screens, we propose to focus on one or two of the identified antiviral factors, selected due to the potency of inhibition in natural settings. We will then execute a variety of molecular virology experiments to reveal the molecular details of how the identified factors block HBV/HDV.We hypothesize that variation in the sequence or amount of the defences that block HBV/HDV helps determine how successful interferon therapies are. Moreover, we believe that variation in our defences influences susceptibility to HDV coinfection. Thus, we plan to examine the levels and sequences of the identified defences, in patients that do and do not respond to interferon therapy. Similarly, we will compare the sequences and levels of defences in patients with and without HDV coinfection. In this way, we aim to reveal the contribution that individual defences make in suppressing HBV and/or HDV. Applications and benefits: Within the timeframe of this award, we plan to shed light on an important area of HBV biology and unlock new avenues of research in this field. In the longer term, our research defining how IFNs inhibit HBV and HDV could inform the design of novel prognostic tests and devices. Eventually (over many years), it is hoped that understanding our natural antiviral defences will lead to these defences being harnessed or mimicked in novel antiviral therapies.

背景：慢性乙型肝炎病毒（HBV）感染是世界范围内肝硬化和肝细胞癌的主要原因。丁型肝炎病毒（HDV）只能在hbv感染的细胞中完成其生命周期。因此，HDV仅在HBV感染的个体中观察到，这种HBV和HDV共同感染加重了HBV相关的发病机制。尽管大多数人在没有任何临床干预的情况下抑制HBV，但约10%的人将成为慢性感染的“携带者”，由此产生的疾病负担是一个主要的全球卫生问题（每年造成约90万人死亡）。I型干扰素已成为慢性HBV感染的标准治疗方法。然而，应答率可能低至30%，因此有必要更好地了解为什么有些人对IFN治疗有反应，而有些人则没有。目的：干扰素刺激数百种基因的上调，这究竟是如何抑制HBV/HDV的，哪些干扰素刺激基因（isg）决定了干扰素治疗的临床结果，这些在很大程度上是未知的。我们建议识别和表征干扰素刺激的防御，这是I型干扰素促进抑制HBV/HDV能力的基础。方法：为了揭示介导HBV和HDV抑制的个体宿主基因，我们将进行筛选，同时测量数百个个体isg抑制HBV和HDV的能力。我们的研究团队由HBV和HDV传播专家（来自日本东京国立传染病研究所（NIID））和ISG筛查专家（位于英国格拉斯哥MRC大学病毒研究中心（CVR））组成。这种综合的专业知识应有助于快速鉴定抑制HBV和HDV的基因。在这些筛选之后，我们建议将重点放在一个或两个已确定的抗病毒因子上，这些因子是根据自然环境中抑制的效力而选择的。然后，我们将执行各种分子病毒学实验，以揭示鉴定因子如何阻断HBV/HDV的分子细节。我们假设阻断HBV/HDV的防御序列或数量的变化有助于决定干扰素治疗的成功程度。此外，我们相信我们防御系统的变异会影响对HDV合并感染的易感性。因此，我们计划在对干扰素治疗有反应和没有反应的患者中检查已识别防御的水平和序列。同样，我们将比较合并HDV感染和未合并HDV感染患者的防御序列和水平。通过这种方式，我们旨在揭示个体防御在抑制HBV和/或HDV方面的作用。应用和益处：在该奖项的时间框架内，我们计划阐明HBV生物学的一个重要领域，并在该领域开辟新的研究途径。从长远来看，我们的研究定义了ifn如何抑制HBV和HDV，可以为新型预后测试和设备的设计提供信息。最终（经过许多年），人们希望了解我们的天然抗病毒防御将导致这些防御在新的抗病毒治疗中被利用或模仿。

项目成果

Human cytomegalovirus evades ZAP detection by suppressing CpG dinucleotides in the major immediate early 1 gene

• DOI: 10.1371/journal.ppat.1008844
• 发表时间: 2020-09-01
• 期刊: PLOS PATHOGENS
• 影响因子: 6.7
• 作者: Lin, Yao-Tang;Chiweshe, Stephen;Grey, Finn
• 通讯作者: Grey, Finn

BTN3A3 evasion promotes the zoonotic potential of influenza A viruses

• DOI: 10.1038/s41586-023-06261-8
• 发表时间: 2023-06-28
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Pinto, Rute Maria;Bakshi, Siddharth;Palmarini, Massimo
• 通讯作者: Palmarini, Massimo