BOVINE RESPIRATORY DISEASE COMPLEX (BRDC) IS A LEADING CAUSE OF MORBIDITY AND MORTALITY IN THE U.S. CATTLE INDUSTRIES. ECONOMIC COSTS TO THE WORLDWIDE CATTLE INDUSTRY DUE TO BRDC HAVE BEEN ESTIMATED AS HIGH AS $3 BILLION ANNUALLY. DESPITE WIDESPREAD USE OF VACCINES AND ANTIBIOTICS, THE INCIDENCE OF BRDC HAS REMAINED UNCHANGED FOR MORE THAN TWO DECADES. THERE IS A SIGNIFICANT NEED FOR EFFECTIVE, NON-ANTIBIOTIC TREATMENTS TO PREVENT BRDC IN THE BEEF AND DAIRY INDUSTRIES. THE INNATE IMMUNE SYSTEM IS THE BODY'S FIRST LINE OF DEFENSE AGAINST INFECTION. ITISBROADLY SPECIFIC AND PROVIDES COLLATERAL PROTECTION AGAINST MULTIPLE TYPES OF INVADING PATHOGENS. IN A HEALTHY ANIMAL, THE INNATE IMMUNE SYSTEM PREVENTS MOST RESPIRATORY INFECTIONS. HOWEVER, STRESS OR INFECTION CAN IMPAIR THE ABILITY OF THE INNATE IMMUNE SYSTEM TO PROTECT FROM DISEASE. THE IDEA OF COUNTERACTING THE KNOWN EFFECTS OF STRESS TO ENHANCE AN ANIMAL'S INNATE STATE OF DISEASE RESISTANCE IS APPEALING. THEREFORE, INCREASING ATTENTION HAS TURNED TO THE DEVELOPMENT OF IMMUNOMODULATORS AS A PROMISING 'ALTERNATIVE' TO ANTIBIOTIC USAGE. WHILE VACCINES TARGET THE ADAPTIVE IMMUNE SYSTEM, IMMUNOMODULATORY TREATMENTS INSTEAD TARGET THE INNATE IMMUNE SYSTEM. BIODEGRADABLE POLYANHYDRIDE NANOPARTICLES (NPS) ARE KNOWN TO PROVIDE SUSTAINED DELIVERY OF BIOLOGICAL MOLECULES AND CAN BE DELIVERED INTRANASALLY, DIRECTLY TO THE RESPIRATORY TRACT. POLYANHYDRIDE NPS CAN BE USED TO DELIVER IMMUNOMODULATORY PAYLOADS, THEREFORE STIMULATING THE INNATE IMMUNE SYSTEM IN THE LUNGS. THIS PROJECT WILL OPTIMIZE THE USE OF INTRANASAL, IMMUNOSTIMULATORY NPS FOR INDUCTION OF A POTENT INNATE IMMUNE RESPONSE IN THE BOVINE RESPIRATORY TRACT. WE WILL GENERATE AND TEST A PANEL OF IMMUNOSTIMULATORY NP FORMULATIONS IN PRIMARY BOVINE CELL CULTURES (OBJECTIVE 1), IN MOUSE MODELS OF DISEASE (OBJECTIVE 2) AND ULTIMATELY IN CATTLE MODELS OF BRDC. AT THE CONCLUSION OF THIS PROJECT, WE EXPECT TO HAVE DEVELOPED AND CHARACTERIZED A NOVEL, NON-ANTIBIOTIC, IMMUNOSTIMULATORY TREATMENT THAT WILL HAVE THE POTENTIAL TO IMPROVE THE OUTCOME OF BRDC IN BEEF AND DAIRY CATTLE.