Rapid evolution and bacterial evasion by a primate cell adhesion protein

与病原体相互作用的蛋白质是动物基因组中进化最快的蛋白质之一，但它们是如何 在保持基本功能的同时能经历如此戏剧性的变化是一个根本的谜团。 癌胚抗原相关细胞黏附分子(CEACAM)家族蛋白具有广泛的 脊椎动物上皮表面的黏附、发育和免疫学作用。除了重要的蜂窝 在功能上，CEACAM是细菌“粘附素”蛋白的靶标，以支持宿主定植。与他们的 重要的内务管理职能，初步分析表明，几个CEACAM正在迅速演变 灵长类，尤其是细菌粘附素识别的结合域。这表明有压力要避免 病原体结合可能加速CEACAM的进化。我假设细菌逃逸推动CEACAM进化 在人类和相关灵长类动物中，对病原体免疫和宿主生理功能产生影响。 这项提议将研究灵长类之间结合的进化和功能后果 利用灵长类动物CEACAM1和致病菌幽门螺杆菌研究CEACAM蛋白和细菌粘附素 幽门螺杆菌作为一个模型系统。CEACAM1-HopQ结合促进幽门螺杆菌感染和癌蛋白注射 CAGA进入宿主细胞，导致胃炎症和癌症的发展。我的初步实验 证明灵长类动物中CEACAM1的快速进化控制着不同物种之间的幽门螺杆菌结合。vbl.使用 系统发育和种群遗传学分析追踪人类和灵长类动物CEACAM的最新进化，目的 我将明确指出宿主群体内黏附识别的进化模式和分子决定因素。 由于识别残基的变化而引起的HopQ结合的改变将在体外用纯化的标记- CEACAM1变异株和携带不同HopQ等位基因的幽门螺杆菌同基因菌株。AIM II将确定HopQ如何 CEACAM1变异通过结合细胞信号影响幽门螺杆菌的致病性 CEACAM1变种。这包括宿主细胞与幽门螺杆菌的联系，促炎细胞因子的诱导 和CagA的磷酸化。AIM III将评估CEACAM1同源二聚化和 CEACAM1变异通过与自然杀伤细胞或 通过CEACAM与嵌合蛋白构建物结合来诱导细胞因子。这项工作将揭示蛋白质是如何 可以进化来躲避病原体，同时保持基本的“家务”功能。结果最终可能 告知幽门螺杆菌感染的治疗以及癌症和其他遗传性疾病的筛查和治疗。 这项工作将在俄勒冈大学进行，由我的联合赞助人S·巴伯博士和 吉列曼。研究环境和培训计划为技术和专业人员提供了大量的机会 发展，包括通过公开介绍和出版 研究、学生辅导和教学，以及负责任行为在研究中的应用。这次培训 该计划将为建立一个独立的研究计划提供良好的准备。

Proteins that interact with pathogens are among the most rapidly evolving in animal genomes, but how they can undergo such dramatic change while maintaining essential functions is a fundamental mystery. Carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family proteins have a wide range of adhesive, developmental and immunological roles at vertebrate epithelial surfaces. Besides important cellular functions, CEACAMs are targeted by bacterial ‘adhesin’ proteins to support host colonization. Contrary to their important ‘housekeeping’ functions, preliminary analyses suggest several CEACAMs are evolving rapidly in primates, particularly in the binding domain recognized by bacterial adhesins. This indicates pressure to avoid pathogen binding may accelerate CEACAM evolution. I hypothesize bacterial evasion drives CEACAM evolution in humans and related primates with consequences for pathogen immunity and host physiologic functions. This proposal will investigate the evolution and functional consequences of binding between primate CEACAM proteins and bacterial adhesins, using primate CEACAM1 and the pathogenic bacteria Helicobacter pylori as a model system. CEACAM1-HopQ binding promotes H. pylori infection and injection of the oncoprotein CagA into host cells, leading to gastric inflammation and cancer development. My preliminary experiments demonstrate that rapid evolution of CEACAM1 in primates controls H. pylori binding between species. Using phylogenetic and population genetic analyses to trace recent CEACAM evolution in humans and primates, Aim I will pinpoint evolutionary patterns and molecular determinants of adhesion recognition within host populations. Altered HopQ binding due to variation at identified residues will be measured in vitro with purified tagged- CEACAM1 variants and isogenic H. pylori strains carrying different HopQ alleles. Aim II will determine how HopQ and CEACAM1 variation impacts pathogenicity of H. pylori using cellular signals of binding to cells expressing CEACAM1 variants. This includes association of host cells with H. pylori, induction of proinflammatory cytokines and CagA phosphorylation. Aim III will assess homodimerization of CEACAM1 homologs and the ability of CEACAM1 variation to alter downstream regulatory signaling using interactions with natural killer cells or the induction of cytokines through CEACAM binding to chimeric protein constructs. This work will reveal how proteins can evolve to evade pathogens while maintaining essential ‘housekeeping’ functions. Results could ultimately inform treatment of H. pylori infections and screening and therapy for cancer and other genetic disorders. This work will be conducted at the University of Oregon under the guidance of my co-sponsors Dr.’s Barber and Guillemin. The research environment and training program provide copious chances for technical and professional development, including training in scientific communication through public presentation and publication of research, student mentorship and teaching, and application of Responsible Conduct in Research. This training program will provide excellent preparation for the establishment of an independent research program.