Rapid evolution and bacterial evasion by a primate cell adhesion protein

灵长类细胞粘附蛋白的快速进化和细菌逃避

• 批准号: 10065935
• 负责人: EmilyClare P Baker
• 金额: $ 6.49万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065935
• 关键词: Adhesions; Adhesives; Affect; Affinity; Alleles; Animals; Antigens; Bacterial Adhesins; Bacterial Infections; Bacterial Proteins; Barbering; Binding; Binding Proteins; Biological Assay; Biological Models; Biotin; CD69 antigen; CEACAM1; Cancer Prognosis; Cell Adhesion Molecules; Cell Culture Techniques; Cell Line; Cell physiology; Cell surface; Cells; Chimeric Proteins; Collaborations; Communicable Diseases; Communication; Conflict (Psychology); Confocal Microscopy; Detection; Development; Dimerization; Disease susceptibility; Dose; Educational process of instructing; Environment; Epithelial; Epithelium; Evolution; Exhibits; Family; Fellowship; Flow Cytometry; Future; Gastritis; Genetic; Genetic Diseases; Genetic Variation; Genome; Helicobacter Infections; Helicobacter pylori; Homodimerization; Housekeeping; Human; Human Cell Line; IL8 gene; Immunity; Immunologics; In Vitro; Infection; Injections; Length; Measurement; Measures; Mediating; Mentorship; Modeling; Molecular; Mutation; Natural Killer Cells; Natural Selections; Oncoproteins; Oregon; Other Genetics; Pan paniscus; Pathogenicity; Pattern; Phosphorylation; Phylogenetic Analysis; Physiological; Pongidae; Population; Population Genetics; Predisposition; Preparation; Primates; Process; Protein Family; Proteins; Publications; Research; Role; Shapes; Signal Transduction; Site; Stomach; Students; Surface; Surface Plasmon Resonance; Testing; Training; Training Programs; Trees; Universities; Variant; Virulence Factors; Western Blotting; Work; adhesion receptor; cancer genetics; cancer therapy; carcinoembryonic antigen-related cell adhesion molecules; cytokine; design; experimental study; genetic analysis; genomic data; host colonization; human disease; individual patient; individualized medicine; insight; malignant stomach neoplasm; pathogen; pathogenic bacteria; pathogenic microbe; pressure; prevent; programs; protein function; response; screening; stable cell line; therapy development; treatment strategy; tumor progression

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.

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，但它们如何 能否在保持基本功能的同时经历如此巨大的变化是一个根本之谜。 癌胚抗原相关细胞粘附分子 (CEACAM) 家族蛋白具有广泛的 除了重要的细胞表面的粘附、发育和免疫作用。 与它们的功能相反，CEACAM 被细菌“粘附素”蛋白靶向以支持宿主定植。 重要的“管家”职能，初步分析表明，一些 CEACAM 正在迅速发展 灵长类动物，特别是在细菌粘附素识别的结合域中，这表明有压力要避免。 病原体结合可能加速 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。 该提案将研究灵长类动物之间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 CEACAM1 和致病菌螺杆菌 CEACAM1-HopQ 结合促进幽门螺杆菌感染和癌蛋白的注射 CagA进入宿主细胞，导致胃部炎症和癌症发展。 证明灵长类动物中 CEACAM1 的快速进化控制着物种之间的幽门螺杆菌结合。 系统发育和群体遗传分析，以追踪人类和灵长类动物最近的 CEACAM 进化，目标 我将查明宿主群体内粘附识别的进化模式和分子决定因素。 由于已识别残基的变化而改变的 HopQ 结合将在体外用纯化的标记-进行测量 CEACAM1 变体和携带不同 HopQ Aim II 的同基因幽门螺杆菌菌株将如何确定 HopQ。 CEACAM1 变异利用与表达的细胞结合的细胞信号影响幽门螺杆菌的致病性 CEACAM1 变体包括宿主细胞与幽门螺杆菌的关联、促炎细胞因子的诱导。 Aim III 将评估 CEACAM1 同源物的同源二聚化和 CagA 磷酸化的能力。 CEACAM1 变异可通过与自然杀伤细胞或 通过 CEACAM 与嵌合蛋白构建体结合诱导细胞因子这项工作将揭示蛋白质如何发挥作用。 可以进化以逃避病原体，同时保持基本的“管家”功能，最终结果可能是这样。 为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提供信息。 这项工作将在我的共同发起人 Dr.’s Barber 和 Dr.’s Barber 的指导下在俄勒冈大学进行。 Guillemin. 研究环境和培训计划为技术和专业人士提供了大量的机会。 发展，包括通过公开展示和出版科学传播培训 研究、学生指导和教学，以及负责任行为在研究中的应用。 该计划将为建立独立研究计划提供良好的准备。