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

基本信息

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

项目摘要

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。该病毒可以从这些宿主感染家禽，并且是家禽业特别关注的问题，感染可能导致高死亡率。这反过来又会危及食品供应链，而疫情爆发也有可能影响人类健康。家禽中禽流感（AI）的爆发表现出多种疾病严重程度，从轻微症状到迅速死亡。特别值得关注的是高致病性禽流感（HPAI）的爆发。迄今为止，只有 H5 和 H7 HA 亚型的 AIV 引起了 HPAI 的爆发。 HPAI 可以直接从野生鸟类引入，但更常见的是与祖先低致病性禽流感 (LPAI) 疾病严重程度的增加有关。高致病性表型的获得与 HA 中多碱基切割位点 (PBCS) 的引入有关。 HA必须被裂解才能被激活，而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，并导致全身性传播和死亡。然而，获得 PBCS 不足以在所有情况下增加病毒的致病性，并且一些具有 PBCS 的 H5/H7 病毒在鸟类中表现出低致病性表型。因此，迫切需要了解影响 HPAI 表型获得的其他因素，以便更准确地评估与新出现的 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 M42 变体通过多种机制在 LPAI 向 HPAI 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称为 M42 的 M2 变体，它与 M2 的胞外结构域仅略有不同。这一微小的差异足以导致 M42 相对于 M2 的亚细胞定位向高尔基体的转移。我们将检验以下假设：M42 亚细胞定位的改变对于调节 HA 活性很重要，并且 M42 表达水平可能会影响高致病性表型的获得。 M2 已被提议构成用于人类和家禽的通用疫苗的基础，该疫苗利用了 M2 的胞外结构域在病毒亚型中保守的事实。由于 M42 的胞外结构域与 M2 不同，因此 M42 的表达也被确定为流感病毒在细胞培养研究中逃避针对 M2 的抗体抑制的机制。迄今为止，还没有在鸟类中进行研究来检验 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。总体而言，在本提案中，我们将研究 (i) 禽流感病毒的 M2/M42 蛋白是否参与其中从低致病性病毒到高致病性病毒的变化，以及 (ii) 从 M2 到 M42 的变化是否对于逃避疫苗反应很重要。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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