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.

流感病毒会感染各种宿主，但其主要储层是野生水产水禽。从这些宿主那里，该病毒可以感染家禽，并且对家禽产业尤其关注，因为感染可能会导致高死亡率。反过来，这可能会危害食物供应链，而爆发也有可能影响人类健康。在家庭家禽中，禽流感（AI）的爆发表现出广泛的疾病严重程度，从轻度症状到快速死亡。特别关注的是高致病性禽流感（HPAI）的爆发。迄今为止，只有AIV的H5和H7 HA亚型引起了HPAI爆发。 HPAI可以直接从野生鸟类引入，但通常与祖细胞低致病性禽流感（LPAI）的疾病严重程度增加有关。高致病性表型的获得与HA中的多重裂解位点（PBC）有关。 HA必须被裂解以被激活，并且PBC的存在意味着该蛋白可以通过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，并导致系统性扩散和死亡。但是，在所有情况下，PBC的获取不足以增加病毒的致病性，而某些具有PBCS的H5/H7病毒在鸟类中表现出低致病性表型。因此，迫切需要了解影响获得HPAI表型的其他因素，以便更准确地评估与新兴AIV感染相关的风险。我们认为，病毒离子通道蛋白M2及其最近被鉴定的称为M42的变体在LPAI中扮演的角色，通过多种机制在HPAI转变中起作用，该建议将探索这一假设。我们最近确定了一种称为M42的M2变体，该变体在其细胞外域中仅与M2略有不同。这种较小的差异足以导致M42相对于M2的次细胞定位转移到高尔基体。我们将检验以下假设：M42的亚细胞定位对于调节HA活性很重要，M42表达水平可能影响高致病性表型的获取。已提出M2构成用于人类和家禽的通用疫苗的基础，该疫苗利用了M2的细胞外域在病毒亚型中保守的事实。由于M42的细胞外结构域与M2不同，因此M42的表达也被确定为一种机制，通过该机制，流感病毒可以通过针对细胞培养研究中针对M2靶向的抗体的抑制作用抑制。迄今为止，尚无研究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。术语中，在此提案中，我们将研究（i）如果Avian流感病毒的M2/M42蛋白参与从低致病性病毒到高度致病病毒和（II）逃避M42的变化中，M42的变化涉及M42的变化。

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