DESPITE THE PROFOUND IMPACT OF EQUINE HERPESVIRUS-1 MYELOENCEPHALOPATHY (EHM), OUR UNDERSTANDING OF HOW AND WHY THE VIRUS CAUSES DISEASE IN THE CNS OF SOME HORSES BUT NOT OTHERS IS LIMITED BEYOND THE KNOWLEDGE THAT IT IS BLOOD CELLS THAT TRANSPORT THE VIRUS FROM THE AIRWAY TO THE CNS. INTERESTINGLY, EHV-4, A CLOSE RELATIVE, DOES NOT INFECT THE BLOOD CELLS OR CAUSE EHM. THIS CLEAR DIFFERENCE IS LIKELY ASSOCIATED WITH DIFFERENCES IN PARTS OF THE VIRUS INVOLVED IN THE INFECTION OF AND MAINTENANCE IN BLOOD CELLS, TRANSPORT OF THE VIRUS AND TRANSFER TO THE CNS, AND INDUCTION OF DISEASE IN THE CNS. WHAT IS UNCLEAR IS WHICH PARTS OF THE VIRUS ARE INVOLVED AND HOW VIRAL AND CELLULAR MECHANISMS AFFECT CNS DISEASE. OUR PROPOSAL SEEKS TO CHALLENGE THE STATUS QUO, BY COMBINING NOVEL IN VITRO MODELS WITH A HORSE INFECTION MODEL.TO ACCOMPLISH THIS, WE WILL EXCHANGE GENES BETWEEN EHV-1 AND EHV-4 AND TEST MUTANTS IN IN VITRO SYSTEMS THAT MODEL THE INFECTION OF THE BLOOD CELLS AND THE CNS (AIMS 1 & 2). WE WILL BUILD UPON THIS ANALYSIS BY INFECTION WITH THE SAME MUTANTS USING A HORSE MODEL (AIM 3) TO CONFIRM THE IMPORTANCE OF THE IDENTIFIED EHV-1 PROTEINS FOR CNS DISEASE IN VIVO.THE PROPOSED COMBINATION OF OUR MODELS REPRESENTS A STEP-BY-STEP ANALYSIS OF CRITICAL EVENTS LEADING TO EHM. THE GENERATED MODELS PROVIDE A RAPIDLY TRANSLATABLE, AND HIGHLY INNOVATIVE APPROACH WITH IMPORTANT POSITIVE IMPACT FOR VALIDATION OF VACCINES OR THERAPEUTICS AND RELEVANCE FOR OTHER VETERINARY ALPHAHERPESVIRUSES.

Michigan State University, East Lansing MI

Investigators