Avian influenza H7N9 virus evolution: defining the impact of internal genes on virus infection in avian and mammalian species

禽流感 H7N9 病毒进化：定义内部基因对禽类和哺乳动物病毒感染的影响

• 批准号: BB/N002571/1
• 负责人: Munir Iqbal
• 金额: $ 85.16万
• 依托单位: The Pirbright Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN002571%2F1
• 关键词: Avian; influenza; H7N9; virus; evolution

In nature, many distinct subtypes of avian influenza (AI) viruses circulate in wild aquatic birds with no consequence to farmed poultry or human health. However, on occasion, these viruses infect domesticated poultry and undergo genetic changes that sometimes result in the emergence of novel viruses with unforeseen biological and pathological characteristics. In recent years, a number of novel AI viruses including H5N1, H5N2, H5N8, H7N1, H7N2, H7N3, H7N7, H7N9, H9N2 and H10N8 have emerged in poultry. H5N1 and H9N2 strains have, within a short space of time, spread to many countries globally, inflicting enormous economic losses together with zoonotic infections of humans with fatal outcomes. In 2013, a novel H7N9 AI virus strain emerged in poultry in China and caused a localized epidemic in humans. The virus is characterised as having a low pathogenicity phenotype and causes subclinical disease and no mortality in chickens. However, human contact with infected birds has led to sporadic severe disease in humans and over 180 fatalities. The virus is now enzootic in poultry in China and possibly other neighboring regions. In order to reduce its zoonotic impacts, large scale culling of infected and potential contact poultry flocks is being carried out in China, with losses so far amounting to over $6.5 billion and predicted to increase substantially. These pre-emptive control measures have become less effective as the spread of the virus in birds widens. The virus continues to evolve and new reassortant genotypes are emerging, carrying genes of other co-circulating poultry influenza virus strains. This exceptionally rapid evolution may potentially drive further increases in virus infectivity, transmissibility and virulence for both poultry and humans; posing great threats to global food security, animal and public health, socioeconomic wellbeing and the environment.Considering the emerging and potentially global consequences of this novel H7N9 virus, there is an urgent need to bring this virus under control, reduce its prevalence in the environment and halt its spread to humans. Developing such control measures requires a comprehensive knowledge base about the nature of infecting virus, such as the viral factors that allow cross-species infection, the rates and mechanism of transmission between birds and from birds to humans and the genetic determinants of virulence in mammalian species compared to birds. The proposed research aims to gain insight into the viral factors that are contributing to the emergence and spread of novel H7N9 virus within poultry, and its transmission to and pathogenicity in humans (using a well-characterised ferret model for human infection). We will also assess the potential threat presented by virus strains that could emerge by similar reassortment events in the future. This project will investigate: (i) how does the internal H9N2 gene cassette change the virological properties of H7N9 influenza virus?; (ii) how do internal gene cassettes from diversified clades of H9N2 viruses impact on H7N9 virus pathogenesis and transmission in avian and mammalian species?; and (iii) how do the H7N9 viruses transmits from poultry to humans?The linking of identified genetic signatures associated with cross-species transmission and virulence with publically available virus genetic data will ultimately help to better predict potential immediate threats. The knowledge gained during this study will enable the design and development of improved tailor-made tools including vaccines, diagnostic reagents and antivirals allowing better control and management of AI infections. Improved control measures together with offering direct benefits may also provide substantial indirect economic, public health, environmental and social benefits to wider communities on both the national and global scale.

在自然界中，许多不同亚型的禽流感（AI）病毒在野生水禽中传播，对养殖家禽或人类健康没有影响。然而，这些病毒有时会感染家禽并发生遗传变化，有时会导致出现具有不可预见的生物学和病理学特征的新病毒。近年来，禽流感病毒在禽类中出现了H5 N1、H5 N2、H5 N8、H7 N1、H7 N2、H7 N3、H7 N7、H7N9、H9 N2和H10 N8等多种新型禽流感病毒。H5 N1和H9 N2病毒株在短时间内传播到全球许多国家，造成巨大的经济损失，并造成人类的人畜共患病感染，造成致命后果。2013年，一种新的H7N9禽流感病毒株在中国的家禽中出现，并在人类中引起局部流行。该病毒的特征是具有低致病性表型，可引起亚临床疾病，但不会导致鸡死亡。然而，人类与受感染鸟类的接触导致了人类的零星严重疾病和180多人死亡。该病毒目前在中国和其他邻近地区的家禽中流行。为了减少人畜共患病的影响，中国正在大规模扑杀受感染和可能接触的家禽群，迄今为止损失超过65亿美元，预计还会大幅增加。随着禽流感病毒在鸟类中的传播范围扩大，这些预防性的控制措施已变得不那么有效。该病毒继续进化，新的耐药基因型正在出现，携带其他共同传播的家禽流感病毒株的基因。这种异常快速的进化可能会进一步增加病毒对家禽和人类的感染性、传播性和毒力;对全球粮食安全、动物和公共卫生、社会经济福祉和环境构成巨大威胁。考虑到这种新型H7N9病毒正在出现并可能造成全球性后果，迫切需要控制这种病毒，减少其在环境中的流行并阻止其向人类传播。制定此类控制措施需要有关于感染病毒性质的全面知识基础，例如允许跨物种感染的病毒因素、鸟类之间和鸟类向人类传播的速率和机制以及与鸟类相比哺乳动物物种中毒力的遗传决定因素。这项拟议的研究旨在深入了解导致新型H7N9病毒在家禽中出现和传播的病毒因素，以及其对人类的传播和致病性（使用一种表征良好的雪貂模型进行人类感染）。我们还将评估未来可能通过类似重配事件出现的病毒株所带来的潜在威胁。本项目将研究：（i）内部H9 N2基因盒如何改变H7N9流感病毒的病毒学特性？(ii)来自H9 N2病毒不同分支的内部基因盒如何影响H7N9病毒在禽类和哺乳动物中的致病和传播？及（iii）H7N9病毒如何由家禽传染给人类？将已确定的与跨物种传播和毒力相关的遗传特征与可获得的病毒遗传数据联系起来，最终将有助于更好地预测潜在的直接威胁。在这项研究中获得的知识将有助于设计和开发改进的定制工具，包括疫苗，诊断试剂和抗病毒药物，从而更好地控制和管理AI感染。改进的控制措施，加上提供直接惠益，还可以在国家和全球范围内为更广泛的社区提供大量的间接经济、公共卫生、环境和社会惠益。

项目成果

First molecular characterisation of avian metapneumovirus (aMPV) in Turkish broiler flocks

土耳其肉鸡群中禽间质肺病毒 (aMPV) 的首次分子表征

• 发表时间: 2018
• 期刊: Avian Diseases
• 影响因子: 1.4
• 作者: Bayraktara E

First Molecular Characterization of Avian Metapneumovirus (aMPV) in Turkish Broiler Flocks

• DOI: 10.1637/11915-061818-resnote.1
• 发表时间: 2018-12-01
• 期刊: AVIAN DISEASES
• 影响因子: 1.4
• 作者: Bayraktar, E.;Umar, S.;Yilmaz, H.
• 通讯作者: Yilmaz, H.

Amino Acid Residue 217 in the Hemagglutinin Glycoprotein Is a Key Mediator of Avian Influenza H7N9 Virus Antigenicity.

• DOI: 10.1128/jvi.01627-18
• 发表时间: 2019-01-01
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Chang P;Sealy JE;Sadeyen JR;Iqbal M
• 通讯作者: Iqbal M

Antigenic Characterization of Human Monoclonal Antibodies for Therapeutic Use against H7N9 Avian Influenza Virus.

• DOI: 10.1128/jvi.01431-22
• 发表时间: 2023-01-31
• 期刊: Journal of virology
• 影响因子: 5.4

Coinfection of Chickens with H9N2 and H7N9 Avian Influenza Viruses Leads to Emergence of Reassortant H9N9 Virus with Increased Fitness for Poultry and a Zoonotic Potential.

• DOI: 10.1128/jvi.01856-21
• 发表时间: 2022-03-09
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Bhat S;James J;Sadeyen JR;Mahmood S;Everest HJ;Chang P;Walsh SK;Byrne AMP;Mollett B;Lean F;Sealy JE;Shelton H;Slomka MJ;Brookes SM;Iqbal M
• 通讯作者: Iqbal M