**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** RECENT RESEARCH HAS DEMONSTRATED THE IMPORTANCE OF HOST PROTEINS FOR AVIAN INFLUENZA VIRUS (AIV) TRANSMISSION INTO OTHER SPECIES AND THE UNIQUE ABILITY OF SWINE TO PROMOTE AIV INFECTION COMPARED TO OTHER MAMMALS. DESPITE EXTENSIVE CHARACTERIZATION OF DIFFERENCES WITHIN CORRESPONDING HOST PROTEINS BETWEEN MAMMALIAN SPECIES, NO STUDIES HAVE BEEN REPORTED THAT FOCUS SPECIFICALLY ON NATURAL HOST VARIATION PRESENT WITHIN SWINE AND THE IMPACT ON AIV INFECTIVITY. GIVEN THE IMMENSE ROLE THAT DOMESTIC PIGS PLAY IN THE ADAPTATION OF AIV FOR MAMMALIAN HOSTS, IDENTIFICATION OF GENE VARIANTS THAT AFFECT SWINE SUSCEPTIBILITY TO AIV WOULD PROVIDE A PLAUSIBLE AVENUE FOR LIMITING THE EMERGENCE OF NOVEL INFLUENZA STRAINS. THEREFORE, THE OVERALL GOAL OF THIS RESEARCH IS TO IDENTIFY GENETIC VARIANTS WITHIN SWINE THAT AFFECT AIV REPLICATION FOLLOWING INFECTION. SPECIFICALLY, THIS STUDY WILL FOCUS ON TWO HOST PROTEINS BELONGING TO THE ACIDIC LEUCINE-RICH NUCLEAR PHOSPHOPROTEIN 32 (ANP32) GENE FAMILY, ANP32A AND ANP32B. FIRST, WE WILL OBTAIN SEQUENCES FROM ~1,000 PIGS TO UNCOVER GENE VARIANTS PRESENT ACROSS DIVERSE DOMESTIC POPULATIONS. SECOND, WE WILL USE GENE EDITING TO GENERATE VARIANT CELL LINES IN COMBINATION WITH FLUORESCENCE-BASED ASSAYS TO QUANTIFY THE EFFECT OF EACH GENE VARIANT ON VIRAL REPLICATION FOR DIFFERENT AVIAN INFLUENZA STRAINS. THE OUTCOMES OF THIS RESEARCH WILL DIRECTLY BENEFIT SWINE PRODUCERS BY INCREASING ANIMAL WELFARE THROUGH POTENTIAL GENETICS-BASED PREVENTION STRATEGIES AND ALTERNATIVE SOLUTIONS TO SUBOPTIMAL VACCINATION REGIMES. ADDITIONALLY, THIS RESEARCH HAS THE POTENTIAL TO REACH BEYOND SWINE AND INTO THE REALM OF HUMAN HEALTH. AS SWINE ARE KNOWN RESERVOIRS AND SUSPECTED MIXING VESSELS FOR DIVERSE INFLUENZA SUBTYPES, DECREASING THE ABILITY FOR AIV TO SURVIVE AND ADAPT WITHIN SWINE WOULD LIKELY REDUCE THE EMERGENCE OF NOVEL PATHOGENIC STRAINS WITH POTENTIAL FOR HUMAN INFECTION AND/OR PANDEMIC TRANSMISSION.