Understanding animal health threats from emerging H5 high pathogenicity avian influenza viruses

高致病性禽流感病毒（HPAIV）是对动物健康的重大负担，具有人类感染的风险，需要在全球范围内持续监测和控制。在过去的两个冬季，HPAIV在英国和欧洲的入侵显著增加。在2020/21季节，在英国（24个）和爱尔兰（2个）发现了26个受感染的家禽场所（IPs）， 300多只野鸟检测呈阳性，创下了当时的疫情季节记录。2020/21年暴发以HPAIV H5N8亚型的检测为主，尽管在家禽中发现了其他H5亚型的暗流，包括H5N5，在野生鸟类中也发现了H5N1和H5N3。在这个季节之后，由于2021/22年的新入侵，病例大幅增加，全英国有超过100个ip，都是由H5N1 HPAIV引起的。在2021/22年期间，800多只野鸟H5N1病毒检测呈阳性，只有一只野鸟检测到H5N8病毒。该项目针对HPAIV在英国（及其他地区）的极端出现，以提高我们对HPAIV的理解，以帮助减轻入侵并改进未来预防策略的方法。工作包（WP1）旨在提高对这些病毒在野生鸟类和家禽中的传播动力学的认识。通过进行生物采样和数据分析，我们将设计更有效的、基于风险的监测计划，并在野生鸟类和家禽界面建立相互作用模型，确定高风险的地理地点和野生鸟类种群，以及与农场入侵的联系。产出将使人们能够更好地了解感染源、野生水禽以及促使疾病从该源侵入家禽部门的因素。WP2旨在评估近年来在英国检测到的hpaiv的抗原多样性，在没有疾病的情况下，在野生水禽和家禽中，在低致病性aiv共循环的背景下。hpaiv的相继出现表明，2020/21年之前对H5N8病毒的免疫不足以防止2021/22年期间H5N1的出现和优势。本工作清单将定义抗体对不同病毒表面蛋白的反应如何影响病毒出现的可能性。这种感染的特征将利用从自然和实验感染中获得的感染后抗血清来研究免疫逃逸。病毒中被确定为在逃逸突变体出现中起重要作用的区域将被进一步研究，以确定在宿主免疫反应靶向的病毒蛋白中弯曲存在的位置。这将有助于开展重点研究，帮助我们了解哪些因素可能影响未来的缓解战略。最后，将在WP3中评估病毒表面蛋白之外驱动不同疾病结果的因素。在这里，将开发新的系统来评估病毒传染性和宿主范围，这反过来将增强我们对病毒-宿主相互作用的理解，并定义内部病毒蛋白的作用，这对病毒复制至关重要，驱动病毒多样性和随之而来的疾病结果的出现。WP3将利用WP1和WP2的产出来检查驱动病毒变体出现的机制，从而实现对不同宿主的差异适应。将开发实验系统，使病毒复制机制的各个组成部分能够被评估和比较，利用我们在实验室中产生病毒的能力来确定遗传规格。将评估最小感染剂量和相关生长动力学，以完善动物模型的工作。利用来自英国各地不同实验系统的专业知识，利用一系列实验室设施，合作伙伴将在各个工作项目之间建立联系，以产生有影响力的产出，以加强我们对这些新出现的病原体的理解。

High pathogenicity avian influenza virus (HPAIV) is a significant burden on animal health, with a risk of human infection that demands continuous monitoring and control globally. Incursions of HPAIV into the UK and Europe have increased significantly in the last two winter seasons. During the 2020/21 season, 26 infected poultry premises (IPs) were detected across the GB (24 IPs) and NI (2 IPs) with over 300 wild birds testing positive, a record outbreak season at that time. The 2020/21 outbreak was dominated by the detection of the HPAIV H5N8 subtype, although an undercurrent of alternative H5 based subtypes was detected including H5N5 in poultry, and H5N1 and H5N3 also being detected in wild birds. This season was then followed by a significant escalation in cases due to new incursions during 2021/22, with over 100 IPs across the UK, all caused by H5N1 HPAIV. During 2021/22, more than 800 wild birds have tested positive for H5N1 virus, with just a single wild bird detection of H5N8. This project targets this extreme emergence of HPAIV in the UK (and beyond), to improve our understanding of HPAIVs to help mitigate incursions and refine approaches to future prevention strategies.Work-package (WP1) aims to improve the understanding of HPAIV transmission dynamics for these viruses in both wild birds and domesticated poultry. By undertaking biological sampling and data analysis we will design more effective, risk-based surveillance programmes and model interactions at wild bird and poultry interfaces, defining geographical sites and wild bird populations of high risk, and linkages to farm incursions. Outputs will enable a greater understanding of the reservoir of infection, wild waterfowl, as well as factors that drive incursion of disease from this reservoir into the poultry sector.WP2 aims to assess antigenic diversity across the HPAIVs detected in the UK in recent years in context of co-circulating low pathogenicity AIVs, in the absence of disease, both in wild waterfowl and poultry. The sequential emergence of HPAIVs suggests that prior immunity from 2020/21 to H5N8 virus was insufficient to prevent emergence and dominance of H5N1 during 2021/22. This WP will define how antibody responses to different virus surface proteins impact upon the potential of virus emergence. This feature of infection will utilise post-infection antisera derived from natural and experimental infection to study immune escape. Areas of the virus that are identified as being important in the emergence of escape mutants will be further investigated to define where flex exists within viral proteins targeted by the host immune response. This will enable focused studies that will help develop our understanding of what factors might influence future mitigation strategies.Finally, factors that drive differential disease outcomes, outside of the viral surface proteins, will be assessed in WP3. Here, novel systems will be developed to assess viral infectivity and host range which in turn will enhance our understanding of virus-host interactions and define the role of internal viral proteins, critical to viral replication, driving virus diversity and emergence with consequent disease outcomes. WP3 will utilise outputs from WP1 and WP2 to examine the mechanisms that drive the emergence of virus variants, enabling differential adaptation to different hosts. Experimental systems that enable individual components of the viral replicative machinery to be assessed and compared will be developed, utilising our ability to generate viruses in the laboratory to defined genetic specification. Minimal infectious doses and related growth kinetics will be assessed to refine work in animal models. Utilising expertise from across the UK in different experimental systems, with access to a range of laboratory facilities, the partners will link across WPs to generate impactful outputs to enhance our understanding of these emerging pathogens.