** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** SENECAVIRUS A (SVA) HAS RECENTLY EMERGED IN SEVERAL OF THE MAJOR SWINE PRODUCING COUNTRIES WORLDWIDE, CAUSING VD OUTBREAKS IN SWINE THAT ARE CLINICALLY INDISTINGUISHABLE FROM FMD AND OTHER HIGH CONSEQUENCE FADS OF LIVESTOCK. NOTABLY, SINCE THE EMERGENCE OF THE VIRUS IN THE US IN 2015 OVER 3000 OUTBREAKS OF SVA-INDUCED VD HAVE BEEN CONFIRMED. VESICULAR DISEASES ARE AMONG THE MOST IMPORTANT DISEASES OF LIVESTOCK. THE ANNUAL COST OF FMD, FOR EXAMPLE, HAS BEEN ESTIMATED TO AMOUNT BETWEEN $6.5 AND $21 BILLION PER YEAR IN ENDEMIC REGIONS, WHEREAS FMD OUTBREAKS IN DISEASE FREE COUNTRIES (LIKE THE US) COULD COST UP TO $84 BILLION. THE SIMILARITY OF SVA WITH SUCH HIGH CONSEQUENCE FADS AND THE FACT THAT THE VIRUS IS CAPABLE OF ESTABLISHING PERSISTENCE AND A CARRIER STATE IN INFECTED ANIMALS WHICH TRANSMIT THE VIRUS TO OTHER SUSCEPTIBLE ANIMALSHIGHLIGHT THE SIGNIFICANCE OF THE DISEASE. UNDERSTANDING THE MECHANISMS UNDERLYING ESTABLISHMENT AND MAINTENANCE OF SVA PERSISTENCE IS CRITICAL TO IMPLEMENT EFFECTIVE PREVENTION AND CONTROL MEASURES TO MITIGATE THE IMPACT THAT CIRCULATION OF THE VIRUS CAUSES TO THE US LIVESTOCK INDUSTRY.THE MAIN GOALS OF THE STUDY PROPOSED HERE ARE TO ELUCIDATE THE MECHANISMS AND HOST CELL FUNCTIONS EXPLOITED BY SVA DURING PERSISTENCE AS WELL AS TO IDENTIFY VIRAL DETERMINANTS UNDERLYING SVA'S ABILITY TO ESTABLISH AND MAINTAIN LONG-TERM PERSISTENT INFECTIONS.THE OUTCOMES OF THIS STUDY WILL SIGNIFICANTLY IMPROVE OUR UNDERSTANDING OF SVA INFECTION BIOLOGY AND PERSISTENCE AND ARE LIKELY TO SHED LIGHT ON THE PATHWAYS AND MOLECULAR MECHANISMS THAT MAY HAVE ENABLED THE MAINTENANCE AND TRANSMISSION OF THE VIRUS IN THE SWINE POPULATION FOR THE LAST THREE DECADES.A DIRECT APPLICATION OF THE BASIC KNOWLEDGE GENERATED HERE THROUGH THE IDENTIFICATION OF MOLECULAR DETERMINANTS OF SVA PERSISTENCE COULD LEAD TO THE DEVELOPMENT OF SAFER AND HIGHLY EFFICIENT VACCINES DEVOID OF THEIR ABILITY TO ESTABLISH PERSISTENCE.