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

补体系统由超过35个分子组成，它们在消除许多无脊椎动物和脊椎动物物种中的病原微生物方面发挥着至关重要的作用。在哺乳动物中，微生物激活补体系统，导致补体的C3和C5组分激活，导致C3a和C5a过敏毒素的释放。这些分子被视为内源性危险信号，诱导白细胞招募到感染部位，并触发几个关键的先天性免疫过程的激活，这些过程负责破坏各种类型的微生物。在包括鱼类在内的原始脊椎动物中，过敏性毒素及其受体的结构和功能的进化方面几乎一无所知。最近在首席研究员实验室进行的研究表明，对虹鲑鱼中这些分子的研究不仅揭示了过敏性毒素及其受体的保守结构域和生物学作用，而且还揭示了与哺乳动物中未见的关键结构元件和新功能相关的独特功能。这个项目将研究硬骨鱼过敏毒素系统的这些独特的结构和功能方面。更具体地说，这个项目将解决：1)虹鱼过敏毒素受体的分子特征及其进化关系；2)这些受体的配体特异性、细胞分布和调节；以及3)鲑鱼过敏毒素在各种天然免疫过程中的体内作用。更广泛的影响：这些研究将扩大关于过敏性毒素系统的分子进化、结构和功能的知识，同时将为动物和人类健康所必需的与补体相关的新的识别和防御机制提供见解。此外，该项目的完成将在几个重要领域产生更广泛的影响：1)这项研究的实施将导致鱼类免疫学领域的一名研究生和一名博士后研究人员的培训，并将使兽医学生(宾夕法尼亚大学兽医学院)接触到这些学生。学校)到这一新兴的研究领域。2)在更广泛的层面上，该项目产生的成果将有助于水产养殖业，使社会受益，因为更好地了解鱼类免疫系统对水生动物健康部门的发展至关重要。

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.