** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** WHILE IT HAS BEEN DEMONSTRATED THAT SARS-COV-2 CAN INFECT NUMEROUS DOMESTIC AND WILD ANIMALS, THERE IS A SIGNIFICANT GAP IN OUR UNDERSTANDING OF SARS-COV-2 INFECTIONS IN SMALL AND LARGE WILDLIFE SPECIES, PARTICULARLY AS IT RELATES TO (I) THEIR PERMISSIVENESS, (II) THEIR ABILITY TO BECOME RESERVOIRS FURTHER DRIVING THE EMERGENCE OF NOVEL VARIANTS, (III) SPILLOVER/SPILLBACK POTENTIAL TO OTHER ANIMALS AND HUMANS, AND (IV) VIRULENCE OF EMERGING VARIANTS FROM WILDLIFE. CIRCULATION OF SARS-COV-2 IN WILDLIFE IS OF SIGNIFICANT PUBLIC HEALTH CONCERN, WITH A CRITICAL NEED TO IDENTIFY NEW RESERVOIRS/SUSCEPTIBLE SPECIES AND TO STUDY THE HUMAN-ANIMAL INTERFACE. NATURAL INFECTION AND TRANSMISSION OF SARS-COV-2 AMONG WHITE-TAILED DEER (WTD), THE PREDOMINANT CERVID SPECIES IN NORTH AMERICA, HAS CAUSED A SIGNIFICANT PUBLIC HEALTH CONCERN, PARTICULARLY RELATED TO THE POSSIBILITY OF SPILLBACK TRANSMISSION TO HUMANS; THE LATTER HAS NOW BEEN REPORTED IN ONTARIO, CANADA. THERE IS A SIGNIFICANT GAP IN OUR KNOWLEDGE REGARDING MUTATIONS OCCURRING IN INFECTED DEER AND THEIR ROLE IN VIRAL DYNAMICS, FITNESS, PATHOGENICITY AND TRANSMISSIBILITY IN ANIMAL RESERVOIRS AND AT THE ANIMAL-HUMAN INTERFACE. HENCE, THERE IS A NEED TO BETTER UNDERSTAND HOW SARS-COV-2 BEHAVES AND EVOLVES IN WILDLIFE SPECIES, AND IF THESE COULD REPRESENT POTENTIAL RESERVOIRS IN NATURE. IN THIS PROJECT, WE WILL INVESTIGATE THE PATHOGENICITY, TRANSMISSION AND SPILLOVER POTENTIAL OF DEER-ADAPTED SARS-COV-2 VIRUSES IN CELL CULTURE, ALONG WITH MONITORING INFECTION DYNAMICS IN WILD NORTH AMERICAN RODENTS AND WTD. USING BOTH IN VITRO AND IN VIVO EXPERIMENTS, WE WILL ANALYZE THE EFFECT OF DEER ADAPTATION OF SARS-COV-2 IN ITS ABILITY TO SPILLOVER OR SPILLBACK AND ITS EFFECTIVE TRANSMISSION.THIS PROJECT WILL ENHANCE OUR UNDERSTANDING OF SARS-COV-2 DYNAMICS (INCLUDING SUSCEPTIBILITY, ADAPTABILITY AND TRANSMISSION) IN WILDLIFE SPECIES, THE ANIMAL-HUMAN INTERFACE, AND THE RISK OF SPILLBACK/SPILLOVER, AND, THUS, CARRIES A TRIPARTITE SIGNIFICANCE TO US AGRICULTURE (WTD), WILDLIFE AND HUMAN HEALTH, AND IS A CLEAR FIT WITHIN THE ONE HEALTH CONCEPT. IT IS ANTICIPATED THAT THE FINDINGS FROM THIS WORK WILL BE OF BENEFIT TO SCIENTISTS, ANIMAL HEALTH AUTHORITIES AND POLICYMAKERS, STAKEHOLDERS INCLUDING PRIMARILY DEER HUNTERS AND FARMERS, AND TRAINEES IN SCIENCE INCLUDING GRADUATE STUDENTS AND POSTDOCTORAL SCHOLARS.