INFLUENZA IS ONE OF THE MOST IMPORTANT RESPIRATORY DISEASES OF SWINE, CAUSED BY INFLUENZA A VIRUSES (IAV). ALTHOUGH IAV INFECTIONS IN PIGS GENERALLY RESULT IN MILD RESPIRATORY SIGNS, IT CAN SIGNIFICANTLY IMPACT PRODUCTION EFFICIENCY IN SWINE HERDS DUE TO ITS HIGH PREVALENCEAND LEAD TO PRODUCTION LOSSES ESTIMATED TO BE $3 TO $10 PER HEAD. THE EPIDEMIOLOGY OF SWINE IAV IS COMPLEX, WITH MANY GENETICALLY DIFFERENT VIRUSES CO-CIRCULATING IN PIGS IN THE UNITED STATES. HUMAN-TO-SWINE TRANSMISSIONS HAVE BEEN REPORTED FREQUENTLY IN THE PAST DECADES AND DIRECTLY CONTRIBUTE TO THIS CURRENT DIVERSITY OF SWINE VIRUSES, COMPLICATING THE CONTROL OF THE DISEASE. ONE EVENTWAS IDENTIFIED RECENTLY: A NOVEL H3N2 VIRUS OF HUMAN ORIGIN BECAME ESTABLISHED IN SWINE HERDS IN THE U.S. AND IS NOW ONE OF THE PREDOMINANT VIRUSES IN CIRCULATION. DESPITE THE IMPORTANCE OF THESE HUMAN-TO-SWINE SPILLOVER EVENTS, LITTLE IS KNOWN ABOUT THE CIRCUMSTANCES UNDER WHICH HUMAN IAVS TRANSMIT AND BECOME ADAPTED TO SWINE. TYPICALLY, AN INFLUENZA VIRUS HAS TO UNDERGO SPECIFIC MOLECULAR CHANGES TO EFFECTIVELY REPLICATE AND TRANSMIT IN A NEW SPECIES. SUCH CHANGES RESULT FROM PRESSURES IMPOSED BY THE NEW HOST, CREATING BOTTLENECKS THAT LEAD TO THE SELECTION OF VIRUSES WITH ADVANTAGEOUS CHARACTERISTICS. WE HYPOTHESIZE THAT THESE SELECTIVE BOTTLENECKS ALTER THE VIRUS'S MOLECULAR CHARACTERISTICS EARLY ON DURING THE ADAPTATION BETWEEN HUMANS AND SWINE AND THAT THESE PROCESSES ARE DEPENDENT ON SPECIFIC HOST FACTORS. THE OBJECTIVES OF THIS PROJECT ARE TO I) FOLLOW HOW A HUMAN IAV VIRUS EVOLVES GENETICALLY OVER TIME WITHIN AN INDIVIDUAL ANIMAL AND BETWEEN ANIMALS AS IT IS TRANSMITTED IN PIGS; II) EVALUATE IF SPECIFIC COMPONENTS OF THE ANIMAL'S IMMUNE RESPONSE IMPOSE PRESSURE TO RESULT IN VIRUS EVOLUTION; III) EVALUATE HOW GENETIC CHANGES DETECTED ON THE VIRAL SURFACE PROTEINS AFFECT THE VIRUS REPLICATION CHARACTERISTICS. WE WILL EVALUATE THE GENETIC CHANGES OF HUMAN-ORIGIN IAV DURING CONSECUTIVE INFECTIONS IN PIGS. ADDITIONALLY, WE WILL EVALUATE THE VIRUS GENETIC EVOLUTION UNDER PRESSURE FROM A SWINE-SPECIFIC IMMUNE COMPONENT. ANY CHANGES THAT ARE DETECTED WILL BE EVALUATED FOR ITS EFFECT ON VIRUS REPLICATION AND FITNESS. THE RESULTS FROM THIS RESEARCH COULD HELP FILTER SWINE SURVEILLANCE DATA FOR VIRUSES THAT HAVE "ADAPTATION SIGNATURES" AND IDENTIFY NEW SPILLOVER EVENTS THAT ARE LIKELY TO BE SUSTAINED IN PIGS. FURTHERMORE, THIS INFORMATION CAN BE USED TO IMPROVE BIOSECURITY MEASURES THAT COULD DECREASE THE VIRAL SPREAD AND PREVENT THE ESTABLISHMENT OFNOVEL VIRUSES. ULTIMATELY, THIS CAN HELP REDUCE THE ECONOMIC COST OF IAV TO PRODUCERS AND THE SWINE INDUSTRY.