RECENT RESEARCH HAS DEMONSTRATED THE IMPORTANCE OF HOST PROTEINS FOR AVIAN INFLUENZA VIRUS (AIV) TRANSMISSION INTO MAMMALS AND THE UNIQUE CAPACITY OF SWINE TO PROMOTE AIV INFECTION. DESPITE EXTENSIVE CHARACTERIZATION OF DIFFERENCES WITHIN CORRESPONDING HOST PROTEINS BETWEEN MAMMALIAN SPECIES, NO STUDIES HAVE BEEN REPORTED THAT FOCUS SPECIFICALLY ON NATURAL GENETIC VARIATION PRESENT WITHIN DOMESTIC SWINE AND THE IMPACT ON AIV INFECTIVITY. GIVEN THE IMMENSE ROLE THAT DOMESTIC SWINE 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 NATURAL HOST VARIANTS THAT DECREASE THE SUSCEPTIBILITY OF SWINE TO AIV INFECTION. SPECIFICALLY, THIS STUDY WILL FOCUS ON TWO KEY HOST PROTEINS (ANP32A AND ANP32B) KNOWN TO PROMOTE AIV REPLICATION FOLLOWING INFECTION. FIRST, WE WILL OBTAIN DNA SEQUENCES ENCODING THE ANP32A/B PROTEINS FROM MORE THAN 500 PIGS REPRESENTING GENETICALLY DISTINCT AND COMMERCIALLY RELEVANT BREEDS TO IDENTIFY NATURAL GENE VARIANTS. SECOND, WE WILL USE GENE EDITING TO SYSTEMATICALLY MODIFY ANP32A/B IN PIG CELLS AND FLUORESCENCE-BASED FUNCTIONAL ASSAYS TO QUANTIFY THE EFFECT OF HOST GENE VARIANTS ON VIRAL REPLICATION FOR DIFFERENT AVIAN AND SWINE 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 PROTECT HUMAN HEALTH AS WELL BY LIMITING THE EXPOSURE OF WORKERS IN FREQUENT CONTACT WITH DOMESTIC SWINE TO MAMMALIAN-ADAPTED AIV STRAINS CAPABLE OF HUMAN INFECTION.