US-UK BBSRC-NIFA Collab: Evolution of the high pathogenicity phenotype in avian influenza virus

美英 BBSRC-NIFA 合作：禽流感病毒高致病性表型的进化

• 批准号: BB/M027163/1
• 负责人: Paul Digard
• 金额: $ 46.9万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM027163%2F1
• 关键词: US; UK; BBSRC; NIFA; Collab

Influenza A virus can infect a wide range of hosts, but its main reservoir is wild aquatic waterfowl. From these hosts, the virus can infect domestic birds and is of particular concern to the poultry industry, where infection can cause high mortality. This in turn can jeopardize the food supply chain, while outbreaks also have the potential to affect human health.Outbreaks of avian influenza (AI) in domestic poultry show a broad range of disease severity, from mild symptoms to rapid fatality. Of particular concern are outbreaks of High Pathogenicity Avian Influenza (HPAI). To date, only the H5 and H7 HA subtypes of AIV have caused HPAI outbreaks. HPAI can be introduced directly from wild birds, but is more commonly associated with the development of increased disease severity from a progenitor Low Pathogenicity Avian Influenza (LPAI). Acquisition of a high pathogenicity phenotype is associated with introduction of a polybasic cleavage site (PBCS) in HA. HA must be cleaved to be activated, and the presence of a PBCS means the protein can be activated by a broader range of host cell proteases, thus increasing the tissues affected by the virus, and leading to systemic spread and death. However acquisition of a PBCS is insufficient to increase the pathogenicity of the virus in all cases, and some H5/H7 viruses with a PBCS display a low pathogenicity phenotype in birds. Therefore there is an urgent need to understand other factors affecting acquisition of a HPAI phenotype in order to more accurately assess the risk associated with emerging AIV infections. We believe that the viral ion channel protein M2, and a recently identified variant of this called M42, play roles in the LPAI to HPAI transition through a number of mechanisms, and this proposal will explore this hypothesis. We recently identified an M2 variant called M42, which differs only slightly from M2 in its extracellular domain. This minor difference was enough to cause a shift in sub cellular localisation of M42 relative to M2, to the Golgi apparatus. We will test the hypothesis that the altered subcellular localisation of M42 is important for regulating HA activity, and M42 expression levels may affect the acquisition of a high pathogenicity phenotype. M2 has been proposed to form the basis of a universal vaccine for use in human and poultry which takes advantage of the fact that the extracellular domain of M2 is conserved amongst virus subtypes. Since the extracellular domain of M42 is different from M2, expression of M42 has also been identified as a mechanism by which influenza virus can escape from inhibition by antibodies targeted against M2 in cell culture studies. To date, no studies examining whether expression of M42 could provide a mechanism for AIV to overcome this vaccination strategy have been performed in birds.Overall, in this proposal we will investigate (i) if the M2/M42 proteins of avian influenza virus are involved in the change from low pathogenic to highly pathogenic virus and (ii) if the change from M2 to M42 is of importance to escape vaccine responses.

甲型流感病毒可感染多种宿主，但其主要宿主是野生水生水禽。从这些宿主中，病毒可以感染家禽，并且特别受到家禽业的关注，在家禽业中，感染可能导致高死亡率。这反过来又会危及食品供应链，而禽流感的爆发也有可能影响人类健康。家禽中禽流感（AI）的爆发显示出广泛的疾病严重程度，从轻微症状到迅速死亡。特别令人关切的是高致病性禽流感的爆发。到目前为止，只有H5和H7 HA亚型的AIV引起了HPAI的爆发。高致病性禽流感可以直接从野生鸟类中引入，但更常见的是与祖先低致病性禽流感（LPAI）的疾病严重程度增加有关。高致病性表型的获得与HA中多碱基切割位点（PBCS）的引入相关。HA必须被切割才能被激活，PBCS的存在意味着该蛋白质可以被更广泛的宿主细胞蛋白酶激活，从而增加受病毒影响的组织，并导致系统性传播和死亡。然而，在所有情况下，获得PBCS不足以增加病毒的致病性，并且一些具有PBCS的H5/H7病毒在鸟类中显示低致病性表型。因此，迫切需要了解影响获得HPAI表型的其他因素，以便更准确地评估与新发AIV感染相关的风险。我们认为，病毒离子通道蛋白M2，以及最近发现的称为M42的变体，通过多种机制在LPAI向HPAI的转变中发挥作用，本提案将探讨这一假设。我们最近发现了一种名为M42的M2变体，它与M2的胞外结构域仅略有不同。这个微小的差异足以导致M42相对于M2的亚细胞定位转移到高尔基体。我们将测试的假设，改变亚细胞定位的M42是重要的调节HA活性，和M42的表达水平可能会影响收购的高致病性表型。已经提出M2形成用于人和家禽的通用疫苗的基础，其利用M2的胞外结构域在病毒亚型中是保守的这一事实。由于M42的细胞外结构域不同于M2，因此在细胞培养研究中，M42的表达也被确定为流感病毒可以逃避靶向M2的抗体抑制的机制。迄今为止，还没有研究M42的表达是否可以为AIV提供克服这种疫苗接种策略的机制，总之，在本提案中，我们将研究（i）禽流感病毒的M2/M42蛋白是否参与了从低致病性病毒到高致病性病毒的变化，以及（ii）从M2到M42的变化是否对逃避疫苗应答很重要。

项目成果

Comparison of the efficacy of a commercial inactivated influenza A/H1N1/pdm09 virus (pH1N1) vaccine and two experimental M2e-based vaccines against pH1N1 challenge in the growing pig model.

• DOI: 10.1371/journal.pone.0191739
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Opriessnig T;Gauger PC;Gerber PF;Castro AMMG;Shen H;Murphy L;Digard P;Halbur PG;Xia M;Jiang X;Tan M
• 通讯作者: Tan M

Supplementary Text from A brief history of bird flu

禽流感简史的补充文本

• DOI: 10.6084/m9.figshare.7868648
• 发表时间: 2019
• 作者: Lycett S

Compositional biases in RNA viruses: Causes, consequences and applications.

• DOI: 10.1002/wrna.1679
• 发表时间: 2022-03
• 期刊: Wiley interdisciplinary reviews. RNA
• 作者: Gaunt ER;Digard P
• 通讯作者: Digard P

Professor Pete Kaiser 1964-2016.

皮特·凯泽教授，1964-2016。

• DOI: 10.1080/03079457.2016.1251745
• 发表时间: 2016
• 期刊: journal of the W.V.P.A
• 作者: Stevens M