** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** FISH, LIKE HUMANS, HAVE AN IMMUNE SYSTEM THAT PROTECTS THEM FROM PATHOGENS. LIKE US, FISH PRODUCE PROTECTIVE ANTIBODIES AFTER INFECTION, AND THESE ANTIBODIES STOP THE PATHOGEN FROM ATTACKING THE FISH. IN HUMANS AND OTHER MAMMALIAN SPECIES, ANTIBODIES FOUND IN THE BLOOD ARE MAINLY INDUCED IN CERTAIN AREAS OF THE SPLEEN THAT HAVE A VERY WELL DEFINED ORGANIZATION, AND THUS, SUCH STRUCTURES ARE ALSO CALLED ORGANIZED LYMPHOID STRUCTURES. HOWEVER, IT IS BELIEVED THAT FISH DO NOT HAVE SUCH STRUCTURES, AND THUS, IT IS UNKNOWN WHERE ANTIBODY RESPONSES ARE INDUCED IN FISH. RECENT FINDINGS FROM OUR LABORATORY STRONGLY SUGGEST THE PRESENCE OF SEMI-ORGANIZED LYMPHOID STRUCTURES IN THE FISH SPLEEN, WHERE ANTIBODY RESPONSES IN THESE ANIMALS APPEAR TO BE INDUCED. THIS PROJECT WILL STUDY THESE NEWLY DISCOVERED SEMI-ORGANIZED LYMPHOID STRUCTURES AND THEIR ROLE IN THE INDUCTION OF FISH ANTIBODY RESPONSES. MOREOVER, THIS PROJECT WILL STUDY THE MECHANISMS BY WHICH ANTIBODY RESPONSES ARE MADE STRONGER AND MORE EFFECTIVE WITHIN THESE SEMI-ORGANIZED LYMPHOID STRUCTURES. SOME OF THESE MECHANISMS INVOLVE THE SELECTION AND EXPANSION OF KEY B CELL CLONES, THE CELLS THAT PRODUCE ANTIBODIES THAT RECOGNIZE PATHOGENS, AS WELL THE MECHANISMS OF HYPERMUTATION IN ANTIBODIES, WHICH IMPROVE THE AFFINITY OF THESE ANTIBODIES FOR THE PATHOGEN.THE RESULTS OF THIS PROJECT WILL BREAK THE LONG-HELD DOGMA THAT FISH DO NOT HAVE SPECIALIZED LYMPHOID STRUCTURES RESPONSIBLE FOR THE INDUCTION OF ANTIBODY RESPONSES. IMPORTANTLY, THE DISCOVERY OF SUCH STRUCTURES IN HUMANS AND OTHER MAMMALS WAS IN THE PAST A FUNDAMENTAL STEP TO UNDERSTANDING HOW IMMUNE RESPONSES AGAINST PATHOGENS ARE GENERATED. THIS KNOWLEDGE WAS IN TURN USED TO IMPROVE THE EFFICACY OF VACCINES AGAINST HUMAN AND ANIMAL PATHOGENS. THUS, IN ADDITION TO IMPROVING OUR KNOWLEDGE ON HOW FISH FIGHT PATHOGENS THROUGH THE INDUCTION OF ANTIBODY RESPONSES, THE RESULTS GENERATED FROM THIS PROJECT WILL BE CRITICAL IN IMPROVING THE EFFICACY OF FISH VACCINES. IN THAT REGARD, A GROWING NUMBER OF FARMED FISH SPECIES REQUIRE VACCINATION AGAINST DIFFERENT PATHOGENS IN ORDER TO SURVIVE IN FISH FARMS. HOWEVER, MANY OF THE CURRENT FISH VACCINES ARE NOT VERY EFFICACIOUS IN INDUCING STRONG AND PROTECTIVE ANTIBODY RESPONSES. THUS, THE KNOWLEDGE DERIVED FROM THIS PROJECT WILL BE INSTRUMENTAL FOR THE FUTURE DESIGN OF MORE EFFICACIOUS FISH VACCINES. IN THE LONG TERM, THE IMPROVEMENT OF FISH HEALTH THROUGH MORE EFFICACIOUS VACCINES WILL DECREASE FISH LOSSES DUE TO DISEASE IN FISH FARMS, THUS, INCREASING THE AVAILABILITY OF FISH PROTEIN TO THE GENERAL POPULATION AT MORE AFFORDABLE PRICES.