Award details

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

Reference	BB/N002571/1
Principal Investigator / Supervisor	Professor Munir Iqbal
Co-Investigators / Co-Supervisors	Dr Simon Gubbins, Dr John McCauley, Dr Holly Shelton
Institution	The Pirbright Institute
Department	Avian Influenza
Funding type	Research
Value (£)	668,314
Status	Completed
Type	Research Grant
Start date	01/07/2016
End date	30/06/2019
Duration	36 months

Abstract

The emergence of a novel genotype of H7N9 virus threatens human and animal health, global food security and world economies. In order to minimize these impacts, a complete understanding is required of the biological properties of the current and predicted future H7N9 reassortant viruses including virus infectivity, host tissue tropism, cross-species transmission and pathogenesis. This project will investigate the genetic parameters that contribute to H7N9 virus maintenance in poultry and transmission to humans. To address this, advanced molecular virology and animal infection studies will be performed. A series of H7N9 viruses will be generated using reverse genetics that represent circulating viruses in poultry, and some human infection isolates. Due to rapid reassortment with other H9N2 viruses, recombinant viruses that carry H9N2 internal genes of representative current prevalent strains in poultry of different geographical regions will also be generated. A detailed assessment of infectivity and replication of the recombinant viruses using established in vitro virus infection assays will be performed. Viruses exhibiting marked differential biological behavior in vitro will be further evaluated for their pathogenicity and transmissibility in chickens and ferrets (a well characterised model for human influenza infection). The likelihood of increased inter-species transmission of viruses by the airborne route will also be investigated. The air flow from the isolation unit that house the infected chickens will be diverted towards the isolation unit that house uninfected ferrets. Infection parameters such as clinical signs, virus shedding and, in the case of severe disease, post mortem and histopathological findings will provide evidence of virus transmission via air. These approaches ultimately will allow systematic dissection of viral genetic components directly impacting on H7N9 virus tissue tropism, pathogenesis, and transmission in avian and mammalian species.

Summary

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.

Impact Summary

We have seen the global impacts of high pathogenicity avian influenza (AI) viruses. In addition, the recent emergence and enzootic spread of a novel H7N9 virus in China has further threatened poultry production systems, human health, food security, trade and the economy. H7N9, being a low pathogenicity virus, does not cause apparent disease in chickens but handling of infected birds has resulted in fatal human disease. The enormous impact of AIV on poultry production, trade and livelihood of millions of poor farmers and shop keepers is incalculable due to control measures, such as large scale culling of infected and at risk poultry flocks and closing down poultry trade markets and allied poultry industries. However, these pre-emptive measures were unable to prevent the virus becoming enzootic in poultry in China. New and improved tools are most certainly required to control and eradicate such viruses and their development and deployment will require an in-depth understanding of the viral factors driving virus persistence in chickens and transmission to humans. This programme of research will generate and deliver knowledge that will directly impact on AI disease control systems globally. We will undertake integrated and innovative approaches that will analyse the virological parameters leading to H7N9 virus emergence. We will advance the fundamental understanding of influenza evolution, spread and virulence in poultry and humans. Thus, the research will directly benefits human and animal health, the poultry industry and the general public. The objectives of this project are directly aligned with the strategic priorities of BBSRC and other national and international organizations having an interest in disease control including; MRC, Defra, World Organisation for Animal Health (OIE), World Health Organization (WHO), Food and Agriculture Organization of the United Nations (FAO). The research will harness the collaborative efforts and expertise of UK scientists working to improve the control of AIV for sustainable growth of the poultry industry and reduction of zoonotic infection risks. The research will also enhance research capacity and training of the next generation of scientists for multi-disciplinary research that addresses priority concerns of infectious diseases on global health and food security. The outcomes of this research will be communicated to stakeholders via multiple mechanisms including publication of the outcomes on publically available open access information sharing systems. Information will be shared promptly via peer-reviewed open access journals, presentations at conferences and workshops helping to determine the research directions and priorities by the learned societies and funding bodies. The engagement with policy makers and disease control agencies will allow making informed decisions and developing effective strategies to combat the increasing number of emerging AI viruses. The PIs also have experience collaborating with potential beneficiaries outside the immediate academic community, including governmental and non-governmental organizations and the corporate sector. Scientific staff and collaborators involved in the project will exploit as many opportunities as possible to disseminate the research for wider public benefits. This will be achieved by utilising well-established public engagement platforms such as BBSRC Business, periodic global animal health, zoonotic diseases impacting public health and food security teleconference. Staff involved in this project will also be encouraged to be STEM (Science, Technology, Engineering and Mathematics) ambassadors and participate in STEM activities.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Animal Health, Immunology, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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