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种分子组成，这些分子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关键作用。在哺乳动物中，微生物对补体系统的激活导致补体的C3和C5组分的激活，导致C3 a和C5 a过敏毒素的各自释放。这些分子被视为内源性危险信号，诱导白细胞募集到感染部位，并触发几个关键的先天免疫过程的激活，这些过程负责破坏各种类型的微生物。事实上，我们对包括鱼类在内的原始脊椎动物中过敏毒素及其受体的结构和功能的进化方面一无所知。最近在主要研究者实验室进行的研究表明，对虹鳟鱼中这些分子的研究不仅揭示了过敏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特征。本计画将探讨硬骨鱼过敏毒素系统的独特结构与功能。更具体地说，这个项目将解决：1）虹鳟鱼过敏毒素受体的分子特征和它们的进化关系; 2）配体特异性，细胞分布和这些受体的调节;和; 3）鳟鱼过敏毒素在各种先天免疫过程中的体内作用。更广泛的影响：这些研究将扩大过敏毒素系统的分子进化，结构和功能的知识，并将在同一时间，提供洞察到新的补体相关的识别和防御机制，是必不可少的动物和人类健康。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）该研究的执行将导致在鱼类免疫学领域培养一名研究生和一名博士后研究员，并将使兽医学生（宾夕法尼亚大学兽医学院）接触这一新兴的研究领域。2)在更广泛的层面上，该项目的成果将通过促进水产养殖业而造福社会，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.