**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** OVERVIEW. VIRAL EMERGENCE POSES A CONSTANT THREAT TO HUMANS AND ANIMALS AND WE ARE NEITHER ABLE TO PREDICT WHICH VIRUSES WILL EMERGE, NOR WHERE, WHEN, OR WHICH POPULATIONS WILL BE AFFECTED. THE OVERALL AIM OF THIS PROJECT IS TO DETERMINE HOW ENVIRONMENTAL, HOST, AND VIRUS FACTORS INFLUENCE HOST-PATHOGEN INTERACTIONS AND TRANSMISSION DYNAMICS OF POTENTIALLY EMERGING VIRUSES. AVIAN INFLUENZA VIRUSES (AIVS) PROVIDE UNIQUE OPPORTUNITIES TO ADDRESS THIS BECAUSE THEY HAVE JUMPED INTO HUMANS, DOGS, PIGS AND HORSES, WITH SIGNIFICANT CONSEQUENCES ON PUBLIC HEALTH, FOOD SECURITY, AND THE GLOBAL ECONOMY. WE WILL FOCUS ON THE INTERSPECIES TRANSMISSION AND EMERGENCE OF AIVS TO HORSES BECAUSE AIV STRAINS HAVE EMERGED IN HORSE POPULATIONS ON INDEPENDENT OCCASIONS. WE PROPOSE TO PERFORM FIELD WORK IN A WELL-DEFINED ECOSYSTEM THAT FAVOURS AVIAN-TO-HORSE AIV TRANSMISSION AND ALSO TO PERFORM LABORATORY EXPERIMENTS USING AVIAN AND EQUINE INFLUENZA VIRUSES WITH DIFFERENT LEVELS OF EQUINE FITNESS - ABILITY TO INFECT AND TRANSMIT IN HORSES. OUR LABORATORY EXPERIMENTS WILL USE GENETIC ENGINEERING TO CAPTURE CHANGES IN FITNESS DUE TO VIRUS EVOLUTION. RESULTS OBTAINED WILL BE COMBINED IN A MATHEMATICAL FRAMEWORK THAT WILL ENABLE THE ESTIMATION OF RISK OF VIRAL EMERGENCE, INCLUDING THE EFFECTS OF HERD IMMUNITY. THIS MULTIDISCIPLINARY RESEARCH WILL PROVIDE NEW INSIGHTS ON THE MECHANISMS THAT UNDERPIN VIRAL EMERGENCE AND WILL AID THE DESIGN OF MORE EFFECTIVE INTERVENTION MEASURES TO CONTROL FUTURE EVENTS OF VIRAL EMERGENCE.INTELLECTUAL MERIT. THIS PROJECT WILL IMPROVE OUR UNDERSTANDING OF THE GENERAL PRINCIPLES THAT ENABLE PATHOGENS TO JUMP TO AND SPREAD IN NEW HOST POPULATIONS. TO THIS END WE WILL USE AIVS, A MAJOR CAUSE OF DISEASE IN HUMANS AND ANIMALS WORLD-WIDE, AS A MODEL SYSTEM. WE WILL BRING TOGETHER ECOLOGY, EVOLUTIONARY BIOLOGY, VIROLOGY AND MATHEMATICAL MODELLING TO DEVELOP NOVEL ANALYTICAL TOOLS THAT WILL ENABLE THE QUANTIFICATION OF RISK OF INFLUENZA EMERGENCE BASED ON THE COMBINATION OF ENVIRONMENTAL, HOST, AND PATHOGEN-ASSOCIATED FACTORS. THIS WORK WILL ADDRESS THE FOLLOWING RESEARCH QUESTIONS: I) HOW DOES BIRD MIGRATION AND POPULATION SIZE IMPACT INTERSPECIFIC TRANSMISSION OF AIVS TO HORSES; II) HOW DOES CROSS IMMUNITY AFFECT VIRUS SUSCEPTIBILITY AND TRANSMISSION DYNAMICS OF AIVS IN HORSE POPULATIONS; III) WHAT IS THE FITNESS LANDSCAPE OF AIVS IN HORSES; AND IV) WHAT EVOLUTIONARY MECHANISMS (MUTATION AND/OR REASSORTMENT) ARE THE MOST LIKELY TO INCREASE AIV FITNESS IN HORSES IN NATURE?BROADER IMPACTS. THIS RESEARCH WILL GENERATE A MULTIDISCIPLINARY FRAMEWORK TO ASSESS THE RISK OF EMERGENCE OF AVIAN-ORIGIN INFLUENZA VIRUSES IN HORSES, PROVIDING IMPORTANT NEW INFORMATION ON THE RISK OF EMERGENCE OF NOVEL VIRUSES IN HORSES. EQUINE INFLUENZA IS AN ECONOMICALLY IMPORTANT DISEASE IN THE UK, US AND WORLDWIDE. FURTHER, HORSES CAN ACT AS INTERMEDIATE HOSTS OF NOVEL VIRUSES, AS ILLUSTRATED BY THE TRANSFER OF EQUINE INFLUENZA VIRUS INTO DOGS THAT LED TO THE EMERGENCE OF CANINE INFLUENZA IN THE US IN EARLY 2000S. IN BROADER TERMS, MORE ACCURATE RISK ASSESSMENT FRAMEWORKS ARE CENTRAL TO DEVELOPING BETTER PREPAREDNESS MEASURES AGAINST FUTURE EVENTS OF PATHOGEN EMERGENCE. OUR APPROACH CAN BE APPLIED NOT ONLY TO OTHER INFLUENZA VIRUSES SUCH AS PARAMYXOVIRUSES (E.G. NIPAH AND HENDRA) AND CORONAVIRUSES (E.G. MERS AND SARS CORONAVIRUSES). WE WILL TRAIN AND MENTOR AT THE UNDERGRADUATE, GRADUATE AND POSTDOCTORAL LEVEL, INCLUDING MULTIPLE INTERNATIONAL EXCHANGES. TO MAXIMIZE IMPACT, RESULTS FROM OUR RESEARCH WILL BE DIRECTLY COMMUNICATED TO STAKEHOLDERS INCLUDING HEALTH AND AGRICULTURAL AUTHORITIES, ACADEMICS, AND THE HORSERACING INDUSTRY.