GENETIC VARIATION AND THE PRESENCE OF MULTIPLE CO-CIRCULATING GENETIC STRAINS, OR LINEAGES IS THE NORM FOR MANY PATHOGENS, PARTICULARLY FOR RAPIDLY EVOLVING VIRUSES.INTERACTIONS BETWEEN DIFFERENT LINEAGES CAN OCCUR IF INFECTION BY ONE LINEAGE CONFERS PARTIAL CROSS-IMMUNITY TO A RELATED LINEAGE, THUS CREATING THE POTENTIAL FOR IMMUNE-MEDIATED COMPETITION AMONGST CO-CIRCULATING LINEAGES. PARTIAL CROSS-IMMUNITY MAY HELP EXPLAIN EPIDEMIOLOGICAL PATTERNS SUCH AS FLUCTUATIONS IN THE FREQUENCY OF DIFFERENT VIRAL LINEAGES THROUGH TIME AS WELL AS IMMUNE-MEDIATED SELECTION AND EMERGENCE OF NEW GENETIC VARIANTS. THIS STUDY FOCUSES ON THE TRANSMISSION DYNAMICS OF GENETICALLY DIVERSE PATHOGENS, PARTICULARLY IN THE CONTEXT OF LIMITED CROSS-IMMUNITY, IMMUNE-MEDIATED SELECTION, AND HOST POPULATION STRUCTURE. USING A HIGHLY DIVERSE VIRUS,PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME VIRUS (PRRSV), WHICH IS HYPERENDEMIC IN PIG POPULATIONS IN THE U.S., THIS PROJECT INVESTIGATES HOW CONTINUAL VIRAL EVOLUTION AND VARIABLE CROSS-IMMUNITY AMONG GENETIC VARIANTS DRIVES CO-CIRCULATION OF DIFFERENT VIRAL LINEAGES, AND IN TURN SHAPES THE DISTRIBUTION OF DISEASE ACROSS HOST POPULATIONS.GIVEN THE RICH DATA AVAILABLE IN LIVESTOCK HOST-PATHOGEN SYSTEMS, THIS PROJECT WILL PROVIDE NEW INSIGHT INTO MULTI-STRAIN ECOLOGICAL THEORY.IN THIS STUDY, THE RESEARCHERS WILL FIRST EVALUATE HOW PARTIAL IMMUNITY INFLUENCES EVOLUTION WITHIN AND BETWEEN HOSTS USING AN EXPERIMENTAL APPROACH, WHERE QUASI-SPECIES EVOLUTION WILL BE TRACKED VIA NEXT GENERATION SEQUENCING. SECOND, COMMERCIAL SWINE FARMS WITH VARIABLE LEVELS OF IMMUNITY (FROM EITHER PAST INFECTION OR VACCINATION) WILL BE MONITORED LONGITUDINALLY TO QUANTIFY VIRAL EVOLUTION AND INVASION SUCCESS OF NEW PRRSV INTRODUCTIONS IN FIELD SETTINGS. THIRD, USING A DATASET OF EXCEPTIONAL SPATIOTEMPORAL RESOLUTION AVAILABLE THROUGH THE MORRISON SWINE HEALTH MONITORING PROJECT, THE RESEARCHERS WILL QUANTIFY HOW SPATIAL HETEROGENEITIES IN CROSS-IMMUNITY (BASED ON PREVIOUS INFECTION AND/OR VACCINATION) AND POPULATION CONNECTIVITY INFLUENCE CO-CIRCULATION AND INTERACTIONS AMONG VIRAL LINEAGES. FINALLY, MATHEMATICAL AND COMPUTATIONAL MODELS WILL BE USED TO ELUCIDATE HOW SPATIAL AND TEMPORAL VARIATION IN CROSS-IMMUNITY INFLUENCES EVOLUTIONARY DYNAMICS AND THE PERSISTENCE AND SEQUENTIAL DOMINANCE OF DIFFERENT CO-CIRCULATING PRRSV LINEAGES.THE RESEARCHERS WILL APPLY INNOVATIVE ANALYTICAL TOOLS, SUCH AS PHYLODYNAMIC AND NETWORK MODELING, TO ANALYZE HOW SPATIAL HETEROGENEITY IN CROSS-IMMUNITY MAY SHAPE THE SPREAD OF DIFFERENT PRRSV LINEAGES. THESE ANALYTICAL APPROACHES ALSO PROVIDE A FRAMEWORK FOR RESEARCHING LANDSCAPES OF CROSS-IMMUNITY IN OTHER HOST-PATHOGEN SYSTEMS.THIS PROJECT ALSO EXPLORESHOW IMMUNITY-DRIVEN FACTORS, SUCH AS VACCINATION OR PRIOR INFECTION, MAY IMPOSE SELECTIVE PRESSURES AND ALTER TRANSMISSION DYNAMICS FOR MULTI-LINEAGE PATHOGENS.THUS, THIS STUDY ADVANCES OUR UNDERSTANDING OF THE EVOLUTION, TRANSMISSION AND PERSISTENCE OF HIGHLY DIVERSE VIRUSES, AND WILL BRING NEW INSIGHTS FOR DYNAMICS OF OTHER HUMAN AND ANIMAL PATHOGENS.