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

在自然界中，许多不同亚型的禽流感病毒在野生水禽中传播，对养殖的家禽或人类健康没有任何影响。然而，这些病毒有时会感染驯化的家禽，并经历基因变化，有时会导致出现具有不可预见的生物学和病理特征的新病毒。近年来，在禽类中出现了一些新的禽流感病毒，包括H5N1、H5N2、H5N8、H7N1、H7N2、H7N3、H7N7、H7N9、H9N2和H10N8。H5N1和H9N1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，并对人类造成致命后果的人畜共患感染。2013年，在中国的家禽中出现了一种新的H7N9禽流感病毒株，并在人类中引发了局部疫情。该病毒的特点是具有低致病性表型，并导致鸡的亚临床疾病和无死亡。然而，人类与受感染禽类的接触已导致人患上零星的严重疾病，并造成180多人死亡。该病毒目前在中国以及可能其他邻近地区的家禽中流行。为了减少对人畜共患病的影响，中国正在大规模扑杀受感染和潜在接触的禽群，目前损失已达65多亿美元，预计还会大幅增加。随着病毒在禽类中传播的扩大，这些先发制人的控制措施已经变得不那么有效。该病毒继续进化，新的重新组合的基因类型正在出现，携带着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传染性、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病毒的新出现和潜在的全球后果，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。制定这种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、禽类之间以及从禽类向人类传播的比率和机制，以及哺乳动物相对于禽类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，以及它对人类的传播和致病性(使用具有良好特征的人类感染雪貂模型)。我们还将评估未来类似重组事件可能出现的病毒株所带来的潜在威胁。这项计划将探讨：(I)H7N9流感病毒的内部H9N2基因盒如何改变其病毒学特性；(Ii)来自不同种类的H9N2病毒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？以及(Iii)H7N9病毒如何从家禽传播到人类？已确定的与跨物种传播和毒力相关的遗传特征与公开的病毒遗传数据相关联，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禽流感感染。改进的控制措施与提供直接惠益一起，也可能在国家和全球范围内为更广泛的社区提供大量间接的经济、公共卫生、环境和社会惠益。

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.