Developing Rapid Responses to Emerging Virus Infections of Poultry (DRREVIP)

The study of viruses of poultry made important contributions to the development of the modern science of virology, due to the ready availability of infectious materials and experimental subjects and by the fact that the majority of the poultry viruses posed no threat to humans. Subsequently the same factors allowed development of techniques for the assay and propagation of viruses in the laboratory, using eggs then tissue culture. These same techniques then played important roles in mammalian virology. Nowadays poultry virology helps protect us from emerging zoonotic viruses such as H5N1 and West Nile virus. It also helps protect the supply of the most important and universally acceptable sources of animal protein to feed a growing world population. That supply has to be protected throughout the sophisticated modern industry, from elite founder stocks in worldwide (including UK and European) breeder companies right down to the massive, obvious level of broiler and egg production. Infectious threats arise regularly, sometimes from previously unknown viruses.
Less obviously, poultry virology plays major roles in human health and in the Biotechnology and Pharmaceutical industries. Isolation and diagnosis of viruses is often conducted in eggs or avian cells, and some important vaccines (notably seasonal and pandemic influenza vaccines) are produced in them. Diagnosis and isolation of viruses that remain unknown, and their production to make new vaccines, will probably require the development of genetically modified eggs and chicken cells.
The UK has traditionally been strong in poultry virus research, arguably leading to the development of the influenza vaccine and to the discovery of antiviral interferon. It has also contributed extensively to work on emerging viruses. BBSRC plans increased effort in poultry virology in the new National Centre for Livestock Virology at IAH Pirbright, working alongside a new National Avian Research Facility at Roslin, Edinburgh. However, until those facilities are completed, the field faces difficulties in recruitment, retention, succession and critical mass.
This proposal addresses important scientific challenges in the design and development of modified cells to allow better isolation and diagnosis of emerging viruses as well as faster and better production of vaccines against them (to protect global food supply but also to benefit the Biotechnology and Pharmaceutical industries). It will cover endemic and exotic viruses as, in the poultry sector, new viruses rapidly cross national and continental boundaries to become global problems.
More importantly, it will help secure effective capacity in UK poultry virus research in advance of the new facilities. It establishes a small, focussed and focal network of university teams, with considerable experience of poultry virology, to recruit young post-doctoral scientists. It will be supported by a leading, representative researcher each from Roslin and IAH, offering network access to those facilities and assisting in managing the programme. Recruits will be trained in the demands of the academic sector, alongside and in collaboration with biomedical scientists, to publish in high impact journals and regularly aim for academic fellowships, yet they will receive strong guidance in poultry virology (and related disciplines) from their teams and the network, with strong support from the IAH and Roslin. The programme cannot cover all aspects of poultry virology and related disciplines but it is hoped that other centres of excellence with interests in poultry virology (e.g. Edinburgh, Belfast, Liverpool, Warwick, DEFRA's AHVLA) will participate in training and collaborating with those who will form the core of the next generation of UK poultry virologists. At the end, some recruits are expected to join the national poultry research facilities while others will remain in universities, but in strong positions to collaborate with those in the facilities.

Whether emerging viruses present as clinical or sub-clinical, acute or persistent, affects how far they might spread before they are recognised. In either situation, interactions between the virus and cell will be crucial, as they will dictate whether or not the virus will be able to replicate and whether or not it induces the expression of host responses that might be used as key signals of otherwise inapparent infection.

These interactions will be affected by host genetic factors that influence innate antiviral responses, particularly the "cell-autonomous" or "intrinsic" responses, and by virus countermeasures. Consequently, this programme focuses on:

(i) characterizing innate and intrinsic responses, and the influence of different host genetic backgrounds;
(ii) isolating new substrates for virus diagnosis, analysis and propagation (by modifying cells and by producing transgenic chickens);
(iii) studying interactions between known viruses and the innate/intrinsic responses. MDV, ALV-J, IBDV and CAV are good examples of viruses causing sub-clinical and persistent infections. AIV and Newcastle disease virus (NDV) will also be studied because they have well recognised modulators of the mammalian innate/intrinsic responses that are likely to target the chicken (and other avian) responses in broad, but distinct, ways. If AIV were to return to poultry from mammalian reservoirs to which it has become adapted (rather than from ducks, as is usual) it might also be limited by its altered receptor tropism; and
(iv) streamlining recombinant vaccine development by quickly identifying appropriate epitopes and antigens to incorporate into the vaccine (particularly for pathogens with large genomes) that induce suitable responses across different chicken breeds.

In doing so, the programme will create also a cadre of new generation poultry virologists well trained and equipped to tackle the threat posed to global food security by emerging viruses of poultry.

Potential beneficiaries of this research would be:

Commercial vaccine producers.
The work, though directly relevant to producers of poultry vaccines will have ramifications for the vaccine industry in the human sector. Benefits of the work, if it leads (directly or indirectly) to improved conventional live, killed, recombinant or subunit vaccines will be across the board: increased food security, wealth creation (vaccine producers, poultry producers), quality-of-life (reducing risk of pandemic flu, protecting supply of poultry meat and eggs - a key source of nutrition worldwide, protecting from infection).

Poultry Breeders.
Breeders will have new approaches and materials for diagnostic of incipient latent infections that might threaten their flocks.

Poultry Farmers.
Farmers will benefit from access to improved recombinant vaccines. Initially this will be via relatively high technology commercial producers. However, improvements in yield could reduce vaccine costs making them more accessible in developing countries and smaller-scale operations.

Replacement, Refinement and Reduction of Animals in Research (3Rs).
Most of the programme aims to improve and develop cell lines to allow more work with viruses and vaccines in vitro. In particular the technology to be developed in Goal 5 should to reduce animal usage and severity of procedures by early elimination of some vaccine candidates using just a few animals without the need for challenge experiments, leaving only the best vaccine candidates to receive the full and careful analysis using challenge experiments.