BVDV OUTBREAKS BECAME A SIGNIFICANT PROBLEM IN THE 1990S AND IN 2008, BVDV WAS ANNOUNCED AS A RESEARCH PRIORITY FOR USDA. SINCE THEN, AN ESTIMATED 80% OF CATTLE PRODUCERS, INCLUDING A MAJORITY OF FEEDLOT OPERATORS, VACCINATE THEIR CATTLE WITH INACTIVATED OR MODIFIED LIVE VIRAL (MLV) VACCINES TO LIMIT LOSSES FROM BVDV. DESPITE A US REGIONAL AS WELL AS A WORLDWIDE PUSH TO CONTROL THE SPREAD OF BVDV, AN ESTIMATED 59% OF US COW-CALF OPERATORS AND 25% OF DAIRY OPERATORS DO NOT ROUTINELY VACCINATE AGAINST BVDV, CONTRIBUTING TO THE CONTINUED PREVALENCE OF BVDV AND ITS DEVASTATION ON THE US CATTLE INDUSTRY. IN ADDITION TO THE LACK OF ROUTINE CONTROL MEASURES AND PREVENTION, VACCINE EFFICACY AND SAFETY IS QUESTIONABLE DUE TO THE ANTIGENIC VARIATION, MUTAGENICITY AND VARIABLE VIRULENCE OF BVDV STRAINS. US CATTLE PRODUCERS WHO DO VACCINATE, RELY AND TRUST THOSE VACCINATIONS, ASSUMING COMPLETE PROTECTION OF THEIR HERDS; HOWEVER, THE VACCINES ARE NOT 100% EFFICACIOUS. AS EVIDENCE, A STUDY CORRELATING HERD VACCINATION AND CALF BVDV VIRAL TITERS FOUND THAT IN HERDS VACCINATING WITH THE INACTIVE VACCINE, 29.6% OF THEM HAD AT LEAST ONE CALF PERSISTENTLY INFECTED (PI) WITH BVDV AND THE HERDS USING MLV, 20% OF THEM HAD AT LEAST ONE PI CALF.PI ANIMALS HAVE BEEN IDENTIFIED AS THE PRIMARY VECTORS OF BVDV, EXPOSING AND POSSIBLY INFECTING NA&IUML;VE ANIMALS WITHIN THE PI'S VICINITY. AN ESTIMATED 0.2-0.4% OF CATTLE ENTERING A FEEDLOT ARE BVDV PI, EQUATING TO DIRECT EXPOSURE OF APPROXIMATELY 62% OF FEEDLOT ANIMALS TO BVDV. PI ANIMALS THEMSELVES ARE LOW PERFORMING ANIMALS, WEIGHING APPROXIMATELY 75 KG LESS THAN NON-PI CALVES AT WEANING. MOST IMPORTANTLY PI CATTLE SPREAD THE INFECTION TO CATTLE IN PROXIMITY CAUSING IMMUNOSUPPRESSION, SECONDARY INFECTIONS, RESULTING IN MORE PERFORMANCE LOSS AND EXACERBATING THE SEEMINGLY LOW PREVALENCE INTO A LARGER PROBLEM.CATTLE TI WITH BVDV HAVE STUNTED GROWTH, INCREASED SUSCEPTIBILITY TO OTHER INFECTIONS, AND INCREASED MORBIDITY RELATIVE TO UNINFECTEDCALVES. IN A 2008 STUDY, CALVES PREVIOUSLY EXPOSED TO BVDV WERE 8.6-15.1 KG LIGHTER AT WEANING THAN CONTEMPORARY NON-INFECTED CONTROL CALVES. THE INSIDIOUS ASPECT OF TI CALVES IS THAT THEY ARE NOT EASILY DISTINGUISHED FROM UNINFECTED CALVES; HOWEVER, THEY ARE 2.3 TIMES MORE LIKELY THAN UNINFECTED CALVES TO HAVE MORBID EPISODES, CONTRIBUTING TO 56.5% OF A HERD'S MORBIDITY. FROM A POPULATION VIEWPOINT, TI CALVES MAKE UP A HIGHER PROPORTION OF CALVES IN BVDV-INFECTED HERDS. A STUDY PERFORMED ON DAIRY CALVES REVEALED THAT 10% OF THE CALVES WERE TI FOR BVDV COMPARED TO 0.5% PI CALVES. THEREFORE, TI ANIMALS REPRESENT THE GREATEST NUMBER OF CATTLE NEGATIVELY IMPACTED BY BVDV FETAL INFECTIONS.ECONOMIC LOSSES CAUSED BY BRD ARE ASSOCIATED WITH THE COSTS OF TREATMENT AND MORTALITY, BUT ALSO CAN OCCUR THROUGH DECREASED PERFORMANCE IN THE FEEDLOT AND DIMINISHED CARCASS CHARACTERISTICS. CAUSES OF BRD ARE COMPLEX, BUT OFTEN CAN BE ATTRIBUTED TO BVDV AND MANNHEIMIA HAEMOLYTICA (M. HAEMOLYTICA) (REVIEWED IN [13]). MOST BACTERIA, M. HAEMOLYTICA, INCLUDED, ARE NOT ABLE TO INDUCE BRD ALONE WITHOUT OTHER PREDISPOSING FACTORS SUCH AS CONCURRENT OR PRIOR INFECTION WITH BVDV. INFECTIONS SECONDARY TO IMMUNOSUPPRESSION BY BVDV SUCH AS BRD CONTRIBUTE ANOTHER $800-900 MILLION ANNUAL LOSS IN REVENUE. THE ECONOMIC IMPACT OF BVDV IN BEEF AND DAIRY INDUSTRIES DICTATES THE NEED FOR FURTHER RESEARCH TO UNDERSTAND THE DEVELOPMENT AND CONSEQUENCES OF PI AND TI BVDV ANIMALS.THE PROPOSED EXPERIMENTS DIRECTLY TEST THE HYPOTHESIS THAT: INFECTION OF FETUSES WITH BOVINE VIRAL DIARRHEA VIRUS (BVDV) IN UTERO PERMANENTLY ALTERS FETAL GENE EXPRESSION THROUGH EPIGENETIC MECHANISMS RESULTING IN LIFE-LONG IMPAIRED POSTNATAL IMMUNE RESPONSES, THUS RESULTING IN PREDISPOSITION OF BOTH TI AND PI CALVES TO POST-NATAL BOVINE RESPIRATORY DISEASE.AIM 1 IDENTIFIES FETAL GENES REGULATING IMMUNE RESPONSES THAT ARE PERMANENTLY ALTERED-MODIFIED BECAUSE OF FETAL INFECTION WITH BVDV.AIM 2 IDENTIFIES POSTNATAL GENE REGULATING IMMUNE RESPONSES THAT ARE PERMANENTLY ALTERED-MODIFIED BECAUSE OF FETAL INFECTION WITH BVDV.AIM 3 TESTS THE HYPOTHESIS THAT IMPAIRED FUNCTION OF IMMUNE RESPONSE GENES CONTRIBUTES TO MORE DAMAGING EFFECT OF SECONDARY INFECTION WITH BRD. IT NOT ONLY EXAMINES IMMUNE RESPONSE GENES, BUT ALSO EXAMINES FEEDLOT PERFORMANCE AND CARCASS CHARACTERISTICS IN STEERS EXPOSED TO BVDV IN UTERO.THE RESEARCH IS DIRECTLY RELATED TO UNDERSTANDING PROCESSES THAT SUPPORT OR DISTURB HEALTH (BVDV INFECTION AND IMMUNE RESPONSES) IN CATTLE, INCLUDING REDUCING HARMFUL DISRUPTIONS (EPIGENETIC CHANGES IN GENE EXPRESSION) LEADING TO DISEASE. ONE POSITIVE OUTCOME OF THESE STUDIES WOULD BE TO IMPROVE DISEASE PREVENTION THROUGH EDUCATING PRODUCERS ABOUT THE LONG-TERM NEGATIVE RAMIFICATIONS OF PI AND TI WITH BVDV. ALSO, FUTURE DIAGNOSES OF CALVES AT RISK FOR SECONDARY INFECTIONS MAY BE BASED ON THE DISCOVERY OF EPIGENETICALLY MODIFIED GENES IN RESPONSE TO FETAL PI AND TI WITH BVDV. LIKEWISE, DEVELOPMENT OF THERAPEUTIC INTERVENTIONS MAY BE POSSIBLE THROUGH BETTER UNDERSTANDING HOW IMMUNOTOLERANCE IS MANIFEST TO FETAL PI AND HOW EPIGENETIC ALTERATION OF IMMUNE GENES TO FETAL PI AND TI IMPACTS POSTNATAL IMMUNE SUSCEPTIBILITY TO SECONDARY INFECTIONS. FINALLY, THE RESEARCH IS DIRECTLY RELEVANT TO USDA NIFA LONGER-TERM GOALS OF ENHANCING SUSTAINABILITY OF ANIMAL PRODUCTION AGRICULTURAL SYSTEMS.THE INFORMATION GAINED IN THESE STUDIES WILL AID IN THE DESIGN OF IMPROVED DIAGNOSTIC TESTS, CONTROL MEASURES AND THERAPEUTIC AGENTS. ALL OF WHICH IS ULTIMATELY DIRECTED TOWARDS EDUCATING STAKEHOLDERS IN 100% VACCINATION COMPLIANCE AND KEEPING BVDV INFECTED ANIMALS OUT OF PRODUCTION CIRCULATION.