[YY-EEID US-UK XXXX] Evaluating how immunosuppression influences influenza A virus transmission and evolution in wild and domestic birds

'Bird flu', caused by influenza A viruses (IAV), is a threat to the productivity of the poultry industry and to Public Health. Some waterbirds are naturally infected with IAVs, for example ducks, geese and swans, but the viruses can jump into poultry populations, with economically devastating consequences. Infectious bursal disease virus (IBDV) is an infection that can destroy the immune system of birds, causing what is known as immunosuppression. IBDV can worsen IAV infection in chickens: IBDV was found to increase the risk of IAV in chicken flocks, causing birds to shed IAV for longer, and reducing how effective IAV vaccines were. Taken together, these studies suggest that IAV from waterbirds will be able to transmit more easily in a chicken flock that has previously been exposed to IBDV. However, there has been no study of how IBDV affects IAV transmission and evolution in a poultry population, or on the contribution IBDV makes to the spread of other viral infections in waterbird populations.

We plan to define how IBDV affects the IAV incubation period, the length of time birds shed IAV, the amount of IAV they shed, how much IAV it takes before they become infected, and the probablility of uninfected birds from becoming infected when placed in an infected group. This information will then be put into mathematical models that we have developed to define the effect of IBDV exposure on an IAV outbreak in chicken flocks. IBDV exposure may also change how the IAV evolves in the chicken, so we will determine the sequence of the IAV shed from the birds at different times after infection to see how the virus is changing over time.

We also have access to a waterbird population that is subject to intense study and we have already identified IBDV in this population. We have over 2,000 samples from these birds stored that we plan to use to determine how many birds have been exposed to IBDV (the prevalence). We also plan to take more samples from a wider variety of waterbirds and from younger birds (that are more susceptible to IBDV) to investigate this further. We also plan to determine the extent to which the IBDV identified in this population causes disease and how destructive it is to the birds' immune systems. We will also determine the contribution IBDV makes to the spread of avian viruses in waterbirds by determining if there is a correlation with the number and amount of viruses shed and the presence of IBDV.

The new information this project will generate will be used to define how much IBDV-induced immunosuppression contributes to the spread of IAVs in chickens and if it contributes to the spread of viruses in waterbirds. This can be used to influence policy- based decisions in the event of another IAV outbreak to improve control of the disease, for example by improving surveillance of IBDV and improving IBDV vaccination processes. In addition, we think this could be applied to other infections, and that diseases of the immune system could influence the spread and evolution of many viruses in wildlife and domestic animals.

Infectious bursal disease virus (IBDV) is a major cause of immunosuppression in chickens that exacerbates influenza A virus (IAV) pathogenicity, prolongs shedding, reduces vaccine efficacy, and facilitates the adaptation of waterbird IAV to poultry. Moreover, IBDV has been found in waterbird species that are the natural hosts for IAVs. However, there has been neither a quantitative study of how IBDV affects IAV transmission and evolution in poultry, nor on the contribution IBDV makes to the shedding of other viral infections in waterbird populations. We plan to define how IBDV affects IAV transmission parameters in chickens such as the latent and infectious periods, peak shedding titre, mean 50% bird infectious dose, transmission probability, adequate contact rate and R0. These data will then be used in transmission and surveillance simulation models we have developed to determine the impact of IBDV exposure on an IAV outbreak in poultry and the time to detection. IBDV may also alter the evolution of IAV, and we plan to deep sequence IAVs shed from inoculated and contact chickens to evaluate how IBDV exposure influences the IAV population. Moreover, we have access to a wild waterbird population that is subject to intense ornithological study in which we have identified IBDV. We already have over 2,000 samples that we plan to use to determine the prevalence of IBDV, and we plan to sample additional species. We will determine the extent to which the waterbird IBDV causes disease and immunosuppression and the contribution it makes to the transmission of other viruses by determining if there is a correlation with the presence of IBDV and the diversity and titer of viruses shed. This proposal will provide new quantitative data to test the hypothesis that immunosuppression enhances the transmission of viruses in wildlife and domestic species and can be used to influence policy- based decisions in the event of another IAV outbreak to improve disease control.

We have developed transmission and surveillance models that we have applied to poultry populations, and metagenomics sequencing protocols that we have applied to a unique and well-characterised aquatic waterfowl population in order to create new knowledge regarding the impact of infectious bursal disease virus (IBDV) on the transmission and evolution of influenza A viruses (IAV), which are economically important pathogens in agriculture that threaten global food security.

Those who will benefit from the project include:
1.) The UK and US poultry industries, farmers, and the communities in which they live. The data generated in this project will be useful for preventing spread of IAV. At present IAV is controlled in the UK and US through detection and de-population, leading to severe economic losses to the poultry industry. For example, in the US, the 2015 H5 HPAI outbreak cost an estimated $3.3 billion. The data from this proposal will provide a greater understanding of the factors that influence IAV transmission, and the time of IAV detection in a flock. If a history of IBDV infection enhances IAV transmission in poultry flocks and alters the time to IAV detection, then improved IBDV surveillance, improved IBDV vaccination practices and an increased education and awareness of the effect of immunosuppression on the spread of infectious diseases in chickens would likely improve IAV control in poultry, potentially reducing losses to the poultry industry. By improving control of these poultry diseases, farmers will be able to make more money, leading to improved economic resilience and benefiting the communities in which they live.

2.) Individuals and organisations that manage wild bird colonies. The data from this proposal could benefit the health of wild birds, by understanding the factors that lead to viral outbreaks in wild bird colonies such as the Fleet Lagoon.

3.) People concerned with animal welfare. The results from this proposal could be used to raise awareness of the need to maintain a healthy immune status in birds, leading to less morbidity and mortality, thus improving animal welfare.

4.) The public. Should IAV be better controlled, the poultry industries will be more productive, boosting the economy in general. Moreover, if the productivity of the poultry industry improves, there will be more food to feed the growing human population and improve the overall nutritional status of communities. Disease prevention also improves production efficiency, which reduces the inputs needed for production output, meaning better land usage, reduced feed inputs, reduced water use, etc, benefiting society at large.

5.) US and UK veterinary virology & immunology, and ecology & evolution communities. The work to be conducted in this proposal will provide a unique opportunity for two postdoctoral research assistants (PDRAs) in the UK, and a technician and an RA in the US to be trained in a variety of techniques of relevance to studying the ecology and evolution of infectious diseases of importance to agriculture, as well as immunosuppression in animals. The British Society for Immunology have recently revived their Comparative Veterinary Immunology Group with a view to improving the visibility of veterinary immunology given the importance of the "One Health" agenda. This project will be of interest to this community. In addition, the project will provide the opportunity for faculty members to participate in the recruitment, training and mentoring of PDRAs.

6.) UK and US attractiveness for research and innovation. This project drives innovation through international collaboration between three world class institutions (two universities and a research institute) in the USA and the UK, thereby enhancing multidisciplinary collaborative links, building an international network of colleagues, and strengthening the infrastructure for research and education in both countries.