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: 10189481
• 负责人: EmilyClare P Baker
• 金额: $ 6.64万
• 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/10189481
• 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; 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最快发展的蛋白质之一，但它们如何 在维持基本功能的同时，可以进行这种巨大的变化是一个基本的谜。 癌胚抗原相关的细胞粘附分子（CEACAM）家族蛋白具有广泛的范围 脊椎动物上皮表面的粘合剂，发育和免疫学作用。除了重要的细胞 功能，CEACAMs由细菌“粘附蛋白”蛋白靶向以支持宿主定植。与他们相反 重要的“家政功能”功能，初步分析表明，几个CECAM正在迅速发展 私人，特别是在细菌识别的结合结构域中。这表明避免的压力 病原体结合可能会加速CEACAM的进化。我假设细菌进化驱动Ceacam Evolution 在人类中，与病原体免疫和宿主生理功能的后果相关。 该建议将研究灵长类动物之间结合的演变和功能后果 CEACAM蛋白和细菌粘附剂，使用原代CECAM1和致病细菌螺旋杆菌 幽门螺杆菌作为模型系统。 CeCAM1-HOPQ结合促进幽门螺杆菌感染和注射癌蛋白 CAGA进入宿主细胞，导致胃感染和癌症发展。我的初步实验 证明CEACAM1在主要对照中的快速演化H.幽门螺杆菌在物种之间结合。使用 系统发育和种群遗传分析，以追踪人类和私人的最近进化，目标 我将确定宿主种群中粘合剂识别的进化模式和分子决定剂。 由于确定的残留物变化而导致的HOPQ结合改变将在体外用纯化的标记 - CEACAM1变体和伴有不同霍普克等位基因的幽门螺杆菌菌株。 AIM II将决定如何Hopq CEACAM1的变异使用与表达细胞结合的细胞信号影响幽门螺杆菌的致病性 CEACAM1变体。这包括宿主细胞与幽门螺杆菌的关联，促炎细胞因子的诱导 和CAGA磷酸化。 AIM III将评估CEACAM1同源物的同构化和 使用与天然杀手细胞的相互作用或 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 可以在维持基本的“管家”功能的同时逃避病原体。结果最终可能 告知幽门螺杆菌感染以及癌症和其他遗传疾病的筛查和治疗。 这项工作将在我的共同赞助商博士理发师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 开发，包括通过公开介绍和出版的科学沟通培训 研究，学生心态和教学以及负责任行为在研究中的应用。这个培训 计划将为建立独立研究计划提供出色的准备。