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，但它们是如何进化的呢？ 能够在保持基本功能的同时经历如此巨大的变化是一个基本的谜团。 癌胚抗原相关细胞粘附分子（CEACAM）家族蛋白具有广泛的免疫调节活性。 脊椎动物上皮表面的粘附、发育和免疫作用。除了重要的细胞 由于CEACAMs的功能，CEACAMs被细菌“粘附素”蛋白靶向以支持宿主定殖。违背其 重要的“内务”功能，初步分析表明，一些CEACAMs正在迅速发展， 灵长类，特别是在细菌粘附素识别的结合域。这表明有压力避免 病原体结合可加速CEACAM进化。我假设细菌逃避驱动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。 这项计划将调查灵长类动物之间的结合的进化和功能后果 CEACAM蛋白和细菌粘附素，使用灵长类动物CEACAM 1和致病菌螺杆菌 pylori作为模型系统。CEACAM 1-HopQ结合促进H.幽门螺杆菌感染和注射癌蛋白 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CEACAM 1在灵长类动物中的快速进化控制H.物种之间的pylori结合。使用 系统发育和群体遗传分析，以追踪人类和灵长类动物中CEACAM的最新进化，目的 我将指出进化模式和宿主种群内粘附识别的分子决定因素。 由于在鉴定的残基处的变化而改变的HopQ结合将在体外用纯化的标记的- CEACAM 1变异体和同基因H. pylori菌株携带不同的HopQ等位基因。Aim II将决定HopQ如何 CEACAM 1变异影响H. pylori使用细胞信号结合细胞表达 CEACAM 1变体。这包括宿主细胞与H.幽门，促炎细胞因子的诱导 和CagA磷酸化。目的III将评估CEACAM 1同源物的同源二聚化和CEACAM 1同源物的同源二聚化能力。 CEACAM 1变异使用与自然杀伤细胞的相互作用来改变下游调节信号传导，或 通过CEACAM与嵌合蛋白构建体的结合诱导细胞因子。这项工作将揭示蛋白质 可以进化以躲避病原体，同时保持基本的“管家”功能。结果可能最终 对H.幽门螺杆菌感染以及癌症和其他遗传疾病的筛查和治疗。 这项工作将在俄勒冈州大学进行的指导下，我的共同赞助人博士。理发师和 吉耶曼研究环境和培训计划为技术和专业人员提供了丰富的机会 发展，包括通过公开介绍和出版 研究，学生指导和教学，以及研究中负责任行为的应用。本次培训 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.