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4th Periodic Report (12/2021 - 11/2022)

Summary of the context and overall objectives of the project

Avian influenza viruses (AIVs) derived from wild waterbirds cause frequent outbreaks of fowl plague (Highly pathogenic avian influenza, HPAIV) in poultry holdings. During the last 15 years seasonal peaks have been observed in the Northern Hemisphere putting high attention and caution on this virus particularly during winter. In contrast, in the past two years HPAIV were detected in wild birds and poultry all over the year in Europe and other parts of the world like North America or Asia which lead an increased threat the socio-economic life. Several subtypes became endemic in different parts of the world and transmission to mammals including humans was also reported. Viruses circulating in pigs are of great concern in this regard since they can evolve to variants which can overcome the human species barrier like pandemic H1N1 from 2009. Thus, AIVs are of enormous socioeconomic importance and will affect urban and wild life in the future.

Within the DELTA-FLU project crucial work has been done to determine key viral, host related and environmental factors which contribute to infections of wild birds, poultry, and mammals. This research aims to improve knowledge on AIVs by providing tools which enable efficient diagnosis, prevention and control strategies primarily in poultry. Moreover, these findings may be helpful for prediction of zoonotic and pandemic potentials of circulating viruses.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

AIV spreadhighly correlates with the migration of wild birds. To determine the flyways of different wild bird species and the contact between birds from different continents, GSM-GPS loggers were used presenting important opportunities for the investigation of AIV dissemination. As an example, contact of Eurasian wigeons with Chinese waterbirds could be revealed showing unexpected potential of virus transmission across continents. Movement models have been calculated and colleagues from different parts of the world were contacted and informed about wild bird migration routes. In addition, infection models for wild waterbirds have been established to analyze susceptibility and transmission of HPAIV in the natural reservoir. Moreover, mutations in the AIV genome were detected which lead to changes in transmission and virulence on their transmission from wild birds to poultry and vice versa. Since 2021 the Gs/Gd lineage of HPAIV H5 is maintained in wild birds in Northern Europe indicating endemic virus circulation of a highly transmissible HPAIV in Europe.

One important question is how poultry gets infected by wild birds. Since the virus is shed by many bird species and also accumulating in the environment, studies have been performed to analyze risk potentials of AIV incursions. In case of the 2017 H5N8 virus outbreaks in Italy it was found that dependent on the first and second infection wave the wild bird-poultry interface or farm-to-farm transmission played an important role, respectively. In addition, further studies revealed high risk of AIV incursions by close proximity to wetlands, where a high variety of bird species potentially excreting and transmitting the virus could be found. Several studies were conducted analyzing the environmental factors and potential routes of incursion on and between farms like straw bedding, bioaerosols or clothing. HPAIV ingress via water was shown to represent the highest risk for onward spread of infectious virus to naive birds.

To understand host factors which impact on severity of disease, different chicken lines have been infected and their immune responses were analyzed. This revealed different immune response mechanisms leading to differences in susceptibility to AIV infections. With regard to the 3R principles in vitro and in ovo experiments were conducted to test for suitability for partial replacement of animal trials. In addition, establishment and dissemination of new methods will help to address questions on virus host interaction and virus pathogenicity. Transparency of the studies conducted in this project enabled adaptation of protocols to avoid duplication of work and yield better comparability. Intensive cooperation within the project consortium partners led to specific assignment of tasks on the same viruses based on the expertise of different working groups.

Virulence determinants are viral genomic factors which lead to differences in pathogenicity. Analyzing natural pairs of low and high pathogenic avian influenza viruses (with low pathogenic viruses as precursors for mutation into high pathogenic pathotypes) like the H7N7 virus from 2015 which shows a low or a high pathogenicity phenotype depending on its genome constellation or the H5N8 clade A virus from 2014 and its descendant from clade B 2016, effects of mutations and segment exchanges on virulence were analyzed and uncovered.

Moreover, a novel experimental system was developed to predict virulence potential upon structural features of viral proteins. To estimate the possibility for new virus variants and their pathogenicity reassortant viruses have been produced and analyzed. In addition, distribution in different species of host proteases which are essential virus replication in the host organism has been investigated. However, these findings could not fully explain the differences in susceptibility of different bird species. Beside avian hosts also pigs have been investigated since they serve as mixing vessel and can be infected by avian and human derived viruses leading to new, potentially zoonotic viruses like the pandemic H1N1 from 2009.

The results have been published in open access journals as well as conferences to disseminate information and help for better prevention and preparedness in future avian influenza outbreaks.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Bird migration and concomitant spread of AIVs is impacted by climate change. To inform about the migratory routes and to make predictions on AIV outbreaks the establishment of migration models is crucial. They can help to understand the role of wild birds for the dissemination of AIVs but also other pathogens. As shown by the SARS-CoV2 pandemic it will be important to make predictions how viruses, particularly potentially pandemic ones like influenza, can spread and what consequences single local outbreaks may have for global society and economy.

The determination of host related and environmental factors contributing to transmission between bird populations from different continents and especially to poultry holdings is of utmost importance for prevention and preparedness of future influenza pandemics. Current virus evolution leading to HPAIVs which became endemic in several areas globally and causing outbreaks not only in winter but also in summer highlight the importance of this research. The acquired knowledge can be used to be prepared for global influenza outbreaks, monitor evolution of the virus towards higher pathogenicity and better identify the risk for zoonotic spill-over events. Moreover, natural biodiversity is highly affected by human activity, e.g. climate change, and the growing threat of mutating viruses represent a high risk for endangered wild bird populations. In addition, establishing new methods to investigate influenza viruses and to reduce the number of animals used in experimental trials will contribute to increased animal welfare and reduction of CO2 emissions.