HERPESVIRUSES ARE UBIQUITOUS IN NATURE, CAUSING MULTIPLE DISEASES OF IMPORTANCE FOR AGRICULTURAL ANIMALS AND HUMANS. WE STUDY THE DEVASTATING CHICKEN MAREK'S DISEASE (MD) HERPESVIRUS (MDV) THAT COSTS THE POULTRY INDUSTRY AN ESTIMATED $US1-2 BILLION PER YEAR. MDV IS NORMALLY CONTROLLED BY VACCINATION; HOWEVER THESE VACCINES DO NOT PREVENT INFECTION, ONLY REDUCING THE INCIDENCE OF DISEASE. A BETTER STRATEGY WOULD BE TO PREVENT INFECTION BY BLOCKING THE ABILITY OF THE VIRUS TO BE SHED FROM AN INFECTED HOST, OR BY BLOCKING THE VIRUS FROM INFECTING A NEW HOST. THERE IS A SIGNIFICANT GAP IN KNOWLEDGE ON HOW HERPESVIRUSES TRANSMIT FROM HOST-TO-HOST AND SPREAD WITHIN A POPULATION. OUR RATIONALE FOR PERFORMING THIS PROJECT IS TO BETTER UNDERSTAND HOW CERTAIN VIRAL PROTEINS, THAT ARE REQUIRED FOR SPREAD OF HERPESVIRUSES, FACILITATE THIS SPREAD AMONG A POPULATION IN ORDER TO DEVELOP BETTER METHODS OR THERAPIES TO TARGET HERPESVIRUSES.AS MENTIONED ABOVE, MDV CAUSES MD IN CHICKENS, WHILE SIMILAR HERPESVIRUSES VARICELLA ZOSTER (VZV) AND HERPES SIMPLEX (HSV-1) CAUSE CHICKEN POX/SHINGLES AND COLD SORES, RESPECTIVELY, IN HUMANS. WE KNOW THAT HERPESVIRUSES ARE NORMALLY FOUND IN A SINGLE SPECIES AND THUS STUDYING HOST-TO-HOST TRANSMISSION REQUIRES NATURAL ANIMAL MODELS. TO DATE, NO MOUSE VERSIONS OF VZV OR HSV-1 HAVE BEEN IDENTIFIED; THEREFORE, THERE ARE NO EXPERIMENTAL MOUSE SYSTEMS AVAILABLE FOR TESTING NATURAL TRANSMISSION OF HERPESVIRUSES. WE HAVE PREVIOUSLY IDENTIFIED TWO HERPESVIRUS PROTEINS THAT ARE ESSENTIAL FOR CHICKEN-TO-CHICKEN SPREAD OF MDV, ONE BEING GLYCOPROTEIN C (GC) THAT IS CONSERVED IN OTHER HERPESVIRUSES, INCLUDING VZV AND HSV-1. INTERESTINGLY, MDV IS QUITE SIMILAR TO VZV AND HSV-1 PARTICULARLY IN THE CELLS THEY INFECT (EPITHELIAL SKIN CELLS) AND HOW THEY DISSEMINATE IN THE ENVIRONMENT (SHED FROM SKIN). SINCE MDV GC IS REQUIRED FOR TRANSMISSION OF MDV, WE HYPOTHESIZE THAT THE GC PROTEIN OF OTHER HERPESVIRUSES, INCLUDING HUMAN VZV AND HSV-1, ARE IMPORTANT FOR HOST-TO-HOST TRANSMISSION. WE WILL ALSO EXAMINE GC IN OTHER AVIAN HERPESVIRUSES, INCLUDING TURKEY HERPESVIRUS (HVT) THAT CAN AFFECT THE TURKEY INDUSTRY.THE MAIN OBJECTIVE OF THIS PROJECT IS TO DETERMINE THE IMPORTANCE OF THE CONSERVED GC PROTEIN IN HOST-TO-HOST TRANSMISSION THAT WILL HAVE DUAL BENEFITS TO BOTH AGRICULTURALLY RELEVANT AVIAN SPECIES (CHICKENS AND TURKEYS) AND HUMANS. WE WILL USE MANY APPROACHES TO ADDRESS THE MAIN OBJECTIVE. FIRST, WE WILL USE NATURAL HERPESVIRUS-ANIMAL SYSTEMS TO DIRECTLY TEST THE IMPORTANCE OF GC IN HOST-TO-HOST TRANSMISSION. THIS WILL BE ACCOMPLISHED BY INFECTING BIRDS (TURKEYS AND CHICKENS) WITH HERPESVIRUSES THAT LACK THE GC GENE AND DETERMINING WHETHER THE VIRUSES CAN SPREAD TO OTHER BIRDS. SECOND, WE WILL DETERMINE WHETHER SWITCHING THE GC PROTEIN FROM A TURKEY HERPESVIRUS TO A CHICKEN HERPESVIRUS WILL ALTER THE VIRUSES ABILITY TO INFECT TURKEYS OR CHICKENS. THE RECIPROCAL EXPERIMENT WILL ALSO BE PERFORMED IN WHICH THE GC PROTEIN FROM A CHICKEN HERPESVIRUS WILL BE PUT INTO A TURKEY HERPESVIRUSES AND THE VIRUSES ABILITY TO TRANSMIT TO TURKEYS AND CHICKENS WILL BE ASSESSED. THIS WILL ADDRESS THE QUESTION OF WHETHER GC PROTEINS DIRECT THE VIRUS TO INFECT SPECIFIC HOSTS. THIRDLY, WE WILL UTILIZE A MODEL IN WHICH SKIN ORGAN CULTURES (SOCS) ARE OBTAINED FROM HUMAN FORESKINS, OR CHICKEN AND TURKEY SKINS, TO EXAMINE THE ABILITY OF VIRUSES LACKING GC TO REPLICATE IN SKIN. ULTIMATELY, THE GOAL IS TO IDENTIFY CONSERVED MECHANISMS OR TARGETS BY WHICH AVIAN AND HUMAN HERPESVIRUSES UTILIZE THE CONSERVED GC PROTEIN TO FACILITATE SPREAD AMONG THEIR RESPECTIVE POPULATIONS. THESE MECHANISMS OR TARGETS CAN THEN BE TARGETED IN VACCINE OR THERAPY DEVELOPMENT.SOME OF THE PROJECTED OUTCOMES OF THIS WORK IS A BETTER UNDERSTANDING OF THE IMPORTANCE OF THE CONSERVED GC PROTEIN FOR HOST-TO-HOST TRANSMISSION, IDENTIFYING POTENTIAL RECEPTORS OR MOLECULES BY WHICH GC FACILITATES TRANSMISSION, AND DEVELOPMENT OF A SYSTEM IN WHICH TO STUDY ANIMAL AND HUMAN HERPESVIRUSES REPLICATION AND TRANSMISSION AND TEST POTENTIAL THERAPIES OR TREATMENTS.THIS RESEARCH IS EXPECTED TO IMPACT VACCINE AND THERAPY DEVELOPMENT AGAINST AGRICULTURAL IMPORTANT AND HUMAN HERPESVIRUSES BY IDENTIFYING PROTEINS AND/OR MECHANISMS BY WHICH HERPESVIRUSES SPREAD FROM HOST-TO-HOST. IF A CONSERVED VIRAL PROTEIN THAT IS ESSENTIAL FOR TRANSMISSION CAN BE IDENTIFIED AMONG HERPESVIRUSES, THIS COULD SIGNIFICANTLY IMPACT HOW WE TREAT AND PREVENT HERPESVIRAL INFECTIONS IN BOTH AGRICULTURALLY IMPORTANT ANIMALS AND HUMANS.