The UK poultry industry is experiencing severe socio-economic damage and threats from high pathogenicity avian influenza viruses (HPAIVs) H5Nx of clade 220.127.116.11. These viruses pose zoonotic infections risks. The rapid evolution of these viruses is modulating their biological behaviour (epidemiology, host-range, transmission, and pathogenesis) in different avian species. To determine potential risks and improve controls against these emerging and re-emerging viruses requires a comprehensive knowledge base about the nature of prevailing viruses, and an integrated cross-disciplinary approach to studying virus ecology and epidemiology based on understanding virus/host interactions, and the genetic determinants of virulence, transmissibility and antigenicity in wild birds/poultry. This project will investigate how contemporary H5Nx HPAIVs acquire adaptive changes to increase fitness within domestic and wild avian populations. We will define viral and host factors that potentially contribute to increased transmissibility, persistence, and pathogenicity in wild birds and those that enhance their potential to disseminate and manifest disease in poultry. Evolutionary changes drive virological, immunological and zoonotic infection potential of these viruses therefore, our understanding of environmental and molecular correlates required or associated with successful evolution, immune escape, dissemination and maintenance of HPAIVs via migratory populations of wild birds will be developed. Furthermore, we will define molecular markers for successful interspecies transmission and fitness in poultry with severe clinical outcomes. The will provide insights for assessing threats from new and emerging strains, enabling national and international agencies to design and execute contingencies as part of risk mitigation and disease control. This will provide vital information when considering how to invest scarce resources for surveillance design aimed at early warning of the threat.