BOVINE HERPESVIRUS 1 (BOHV-1)IS A MAJOR CATTLE PATHOGEN THAT CAUSES BOVINE RESPIRATORY DISEASE AND SPONTANEOUS ABORTIONS IN INFECTED ANIMALS, LEADING TO ANNUAL LOSSES IN EXCESS OF $1 BILLION IN THE US.SEVERAL VACCINES AGAINST BOHV-1 ARE AVAILABLE BUT ARE NOT ALWAYS PROTECTIVE AGAINST DISEASE, AND IN SOME CASES ACTUALLY INCREASE THE RISK OF SPONTANEOUS ABORTION. THE LATENCY-REACTIVATION CYCLE IS ONE MAJOR COMPLICATING FACTOR IN BOVINE DISEASE AND VACCINE DEVELOPMENT. FOLLOWING ACUTE INFECTION, BOHV-1 ESTABLISHES LIFE-LONG LATENCY IN NEURONAL CELLS, MARKED BY PERIODIC REACTIVATION TO PRODUCTIVE INFECTION. WHILE LITTLE IS KNOWN ABOUT WHAT TRIGGERS REACTIVATION, ENVIRONMENTAL AND PHYSIOLOGICAL STRESS ARE STRONGLY CORRELATED WITH INCREASED REACTIVATION. ADDITIONALLY, INJECTION OF DEXAMETHASONE, A SYNTHETIC STRESS HORMONE, CONSISTENTLY INDUCES REACTIVATION IN LATENTLY INFECTED CALVES. WE NEED TO BETTER UNDERSTANDTHE ROLE THAT STRESS PLAYS IN VIRUS REACTIVATION TO PREVENT DISEASE AND PRODUCE A MORE VIABLE VACCINE.IT HAS BEEN PREVIOUSLY SHOWN THAT SEVERAL KEY VIRUS GENES, INCLUDING BICP0 AND BVP16, ARE REQUIRED FOR EFFICIENT REACTIVATION FROM LATENCY. THIS PROJECT AIMS TO CHARACTERIZE HOW STRESS HORMONES CAN DIRECTLY ACTIVATE THESE GENES, PARTICULARLY DURING REACTIVATION FROM LATENCY. CORTISOL, A STRESS HORMONE, DIRECTLY ACTIVATES THE GLUCOCORTICOID RECEPTOR (GR), WHICH IN TURN A LARGE NUMBER OF GENES. OF NOTE, THE GR ACTIVATES KLF4, WHICH COOPERATES WITH GR TO ACTIVATE SEVERAL VIRAL GENES, INCLUDING BICP0. IN THIS PROJECT, WE WILL CHARACTERIZE HOW GR AND KLF4 ACTIVATE BICP0, BOTH DURING PRODUCTIVE INFECTION AND REACTIVATION FROM LATENCY. THIS WILL DEMONSTRATE A DIRECT CAUSAL LINK BETWEEN STRESS AND REACTIVATION FROM LATENCY. SPECIFICALLY, WE WILL: 1.MEASURE THE ACTIVATION BY GR AND KLF4 OF BOHV-1 ANDBICP0, 2. CHARACTERIZE THE ASSOCIATION OF GR AND KLF4 WITH BICP0, AND 3. IDENTIFY ADDITIONAL GENES ACTIVATED BY GR AND KLF4.THE ULTIMATE GOAL OF THIS PROJECT IS TO BETTER DEFINE THE CAUSAL LINK BETWEEN STRESS AND BOHV-1 REACTIVATION, SO WE BOTH CAN REDUCE BOVINE RESPIRATORY DISEASE AND SPONTANEOUS ABORTION RATES, AND PRODUCE A MORE SAFE AND EFFECTIVE VACCINE AGAINST BOHV-1. THIS WOULD GREATLY REDUCE MORBIDITY AND MORTALITY IN CATTLE HERDS, PROMOTING BETTER ANIMAL HEALTH, AND GREATER OVERALL STABILITY IN THE CATTLE INDUSTRY. THIS WILL BE ACCOMPLISHED BY BOTH VACCINE DEVELOPMENT AND IMPROVED ANIMAL HUSBANDRY TO REDUCE THE EFFECTS OF STRESS AND IT'S ASSOCIATED INCREASE IN DISEASE.