Evolutionary Origins and Novel Roles of Anaphylatoxins and their Receptors in Innate Immune Reactions of Teleost Fish

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The complement system is comprised by more than 35 molecules that play a crucial role in eliminating pathogenic microorganisms in many invertebrate and vertebrate species. In mammals, activation of the complement system by microbes results in the activation of the C3 and C5 components of complement, leading to the respective release of the C3a and C5a anaphylatoxins. These molecules are viewed as endogenous danger signals that induce the recruitment of leukocytes to the site of infection, and trigger the activation of several key innate immune processes that are responsible for the destruction of various types of microbes. Virtually nothing is known about the evolutionary aspects of the structure and function of anaphylatoxins and their receptors in primitive vertebrates, including fish. Recent research carried out in the principal investigator's laboratory has shown that the study of these molecules in rainbow trout has revealed not only conserved structural domains and biological roles of anaphylatoxins and their receptors, but also unique features related to key structural elements and novel functions not seen in mammals. This project will investigate these unique structural and functional aspects of the anaphylatoxin system of teleost fish. More specifically, this project will address: 1) The molecular characterization of rainbow trout anaphylatoxin receptors and their evolutionary relationships; 2) The ligand specificities, cell distribution and regulation of these receptors, and; 3) The in vivo roles of trout anaphylatoxins in various innate immune processes. Broader Impact: These studies will expand knowledge of the molecular evolution, structure and function of the anaphylatoxin system and will, at the same time, provide insights into novel complement-related mechanisms of recognition and defense that are essential to animal and human health. In addition, the completion of this project will have a broader impact in several important areas: 1) Execution of this research will result in the training of a graduate student and a post-doctoral researcher in the area of fish immunology, and it will expose veterinary students (University of Pennsylvania -Vet. School) to this new emerging area of research. 2) On a broader level, the results derived from this project will benefit society by contributing to the aquaculture industry since a better knowledge of the fish immune system is essential to the development of the aquatic animal health sector.