THIS PROJECT IS FOCUSED ON BOVINE RESPIRATORY DISEASE (BRD), ALSO KNOWN AS 'SHIPPING FEVER' OR 'ENZOOTIC CALF PNEUMONIA'. BRD IS ONE OF THE LEADING CAUSES OF DISEASE AND DEATH LOSSES IN BOTH DAIRY AND BEEF CATTLE. ECONOMIC COSTS TO THE CATTLE INDUSTRY DUE TO BRD HAVE BEEN ESTIMATED AS HIGH AS $3 BILLION ANNUALLY DUE TO DEATH LOSSES, REDUCED PERFORMANCE AND COSTS OF VACCINATIONS AND TREATMENTS. BRD IS CAUSED BY MULTIPLE VIRAL AND BACTERIAL PATHOGENS THAT WORK TOGETHER TO CAUSE SEVERE PNEUMONIA. THE IMMUNE RESPONSE TO BRD IS IMPORTANT TO CONTROL THE PATHOGENS, BUT CAN ALSO CAUSE DAMAGE TO THE LUNGS, FURTHER AGGRAVATING THE CONDITION AND ULTIMATELY CAUSING THE ANIMAL MORE ISSUES THAN THE PATHOGEN ITSELF. THIS PROJECT WILL STUDY THE ROLE OF THE HOST IMMUNE RESPONSE IN A MODEL OF BRD AND WILL DETERMINE IF A PHARMACEUTICAL TREATMENT THAT INHIBITS CERTAIN COMPONENTS OF THE HOST IMMUNE RESPONSE WILL IMPROVE THE OUTCOME OF BRD. DEVELOPMENT OF A NONANTIBIOTIC TREATMENT THAT CANREDUCE THE SEVERITY OF BRD IS EXPECTED TO BENEFIT THE ANIMAL BY ALLEVIATING SUFFERING AND EXPEDITING RECOVERY, AND TO BENEFIT THE PRODUCER BY INCREASING ANIMAL PERFORMANCE AND REDUCING THE NEED TO REPEATED TREATMENTS.INTERLEUKIN-17A (IL-17) IS A PRO-INFLAMMATORY CYTOKINE THAT CAN CAUSE IMMUNOPATHOLOGY THROUGH ITS ROLE IN NEUTROPHIL RECRUITMENT AND ACTIVATION. TH17 CELLS ARE CD4 T CELLS THAT SELECTIVELY PRODUCE IL-17. OUR CENTRAL HYPOTHESIS IS THAT INHIBITING IL-17 AND TH17 RESPONSES WILL IMPROVE THE OUTCOME OF BRD IN THE CALF. THE SPECIFIC SCIENCE OBJECTIVES FOR THIS PROJECT ARE: (1) DETERMINE THE IMPACT OF PROPHYLACTIC INHIBITION OF TH17 RESPONSES ON DISEASE OUTCOME AND IMMUNITY TO MANNHEIMIA HAEMOLYTICA INFECTION IN THE CALF; (2) DETERMINE THE IMPACT OF PROPHYLACTIC INHIBITION OF TH17 RESPONSES ON DISEASE OUTCOME AND IMMUNITY TO CO-INFECTION WITH BOVINE RESPIRATORY SYNCYTIAL VIRUS AND M. HAEMOLYTICA IN THE CALF; AND (3) DETERMINE THE IMPACT OF THERAPEUTIC INHIBITION OF TH17 RESPONSES ON DISEASE OUTCOME AND IMMUNITY TO BOVINE RESPIRATORY SYNCYTIAL VIRUS AND M. HAEMOLYTICA CO-INFECTION IN THE CALF.