** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** IT NOW APPEARS CERTAIN THAT SARS-COV-2 WILL PERSIST IN ANIMALS AS LONG AS IT IS PREVALENT IN HUMANS. THE IMPLICATIONS OF MULTIPLE MAMMAL SPECIES CONTRACTING SARS-COV-2 ARE UNCLEAR, BUT MOUNTING EVIDENCE SUGGESTS THAT SOME ANIMALS MAY EXPERIENCE FATAL DISEASE, AND THAT ANIMAL SPECIES WILL SERVE BOTH AS STABLE RESERVOIRS OF VIRAL VARIANTS THAT WERE PREVIOUSLY DOMINANT IN HUMANS, AND AS NEW RESERVOIRS FOR NEW VARIANTS. MANY OF THESE NEW RESERVOIRS ARE COMMON WILDLIFE SPECIES, SUCH AS WHITE-TAILED DEER, DEER MICE AND RED FOX, WHICH OCCUR IN RELATIVELY HIGH ABUNDANCES IN SOME SYSTEMS AND HIGHLIGHT PATHWAYS OF SECONDARY SPILLOVER TRANSMISSION TO HUMANS LIVING IN CLOSE PROXIMITY. TO UNDERSTAND THE FUTURE OF SARS-COV-2 IN MAMMAL COMMUNITIES, THIS PROJECT WILL ADVANCE OUR CURRENTLY LIMITED CAPACITY TO PREDICT ANIMAL HOST SPECIES, NOVEL ZOONOTIC VARIANTS, AND THE POTENTIAL INTERACTIONS AMONG MULTIPLE SPECIES THAT COMPRISE MAMMAL COMMUNITIES. TO ACHIEVE THIS, THIS PROJECT INTEGRATES LEADING EDGEADVANCES IN ARTIFICIAL INTELLIGENCE, VIROLOGY, AND ECOLOGICAL THEORY IN FOUR SPECIFIC AIMS: AIM 1 MAKES PREDICTIONS ABOUT FUTURE ZOONOTIC VARIANTS OF SARS-COV-2 AND THEIR EVOLUTIONARY TRAJECTORIES BY ADVANCING METHODS IN CONTROLLED GENERATIVE AI. AIM 2 PREDICTS WHICH PARTICULAR MAMMALIAN SPECIES ARE SUITABLE HOSTS FOR EXISTING AND FUTURE ZOONOTIC VARIANTS, EXTENDING PREDICTIONS EVEN TO SPECIES FOR WHICH HOST CELL RECEPTOR (ACE2) SEQUENCES ARE STILL UNKNOWN. AIM 3 CONDUCTS SAFE AND EFFICIENT EMPIRICAL VALIDATIONS OF PREDICTIONS MADE IN AIMS 1 AND 2 BY TESTING CELL ENTRY USING A PSEUDOTYPED VIRUS PLATFORM FOR A SUBSET OF ZOONOTIC VARIANTS AND ANIMAL CELL RECEPTORS. AIM 4 ADVANCES THEORY FOR DISEASE TRANSMISSION IN WILDLIFE COMMUNITIES BY BUILDING A FRAMEWORK THAT ACCOUNTS FOR SPECIES DISTRIBUTIONS, THEIR ECOLOGICAL INTERACTIONS (SUCH AS PREDATION AND COMPETITION), AND FINE-SCALE CONTACT PATTERNS THAT INFLUENCE TRANSMISSION AMONG INDIVIDUAL ANIMALS. TOGETHER THESE METHODS ENABLE SPATIALLY EXPLICIT PREDICTIONS ABOUT SARS-COV-2 DYNAMICS IN MAMMAL COMMUNITIES. THIS MODEL WILL BE APPLIED TO THE NORTHEASTERN FOREST COMMUNITY USING 30 YEARS OF DATA FOR MULTIPLE MAMMAL SPECIES AND ONGOING SARS-COV-2 SURVEILLANCE. COLLECTIVELY, THE TOOLS DEVELOPED IN THIS PROJECT WILL LEAD TO THE RAPID PREDICTION AND VALIDATION OF ANIMAL HOSTS FOR CURRENT AND FUTURE VARIANTS OF SARS-COV-2. GIVEN THE PERSISTENT AND GROWING RISK OF ZOONOTIC EMERGENCE FROM ANIMAL HOSTS, THE INNOVATIONS DEVELOPED IN THIS PROJECT WILL ADVANCE RISK ASSESSMENT CAPACITY FOR WILDLIFE, DOMESTIC ANIMALS, AND HUMANS BY HELPING TO PREDICT AND TARGET PARTICULAR VIRUSES, THEIR VARIANTS, AND THEIR MULTIPLE HOST SPECIES, WHILE ALSO INTEGRATING THE DYNAMIC ECOLOGICAL CONTEXT IN WHICH SPECIES INTERACTIONS AND TRANSMISSION CULMINATE TO INFORM ZOONOTIC RISK IN COMPLEX SYSTEMS.