Examining a Unique Contractile Injection System Mediating Host-Microbe Interactions

检查介导宿主-微生物相互作用的独特收缩注射系统

• 批准号: 10672432
• 负责人: Nicholas J Shikuma
• 金额: $ 37.35万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672432
• 关键词: Adult; Amoeba genus; Area; Bacteria; Bacteroides; Binding; Cadherins; Cells; Cryo-electron tomography; Development; Disease; Equilibrium; Eukaryotic Cell; Europe; Family; Fiber; Fluorescence Microscopy; Foundations; Health; Health Promotion; Human; Human Cell Line; Human Microbiome; In Vitro; Inflammatory Bowel Diseases; Inflammatory Response; Injections; Insecta; Investigation; Knowledge; Laboratories; Link; Mediating; Obesity; Organism; Probiotics; Proliferating; Proteins; Structure; Structure-Activity Relationship; Syringes; System; Technology; United States; Work; experimental study; fecal transplantation; gut bacteria; gut microbiome; host-microbe interactions; improved; invertebrate host; microbiome; response

Project Summary Bacteria within the human microbiome typically benefit the host. However, an imbalance of some bacteria groups such as Bacteroidales can lead to diseases like obesity and inflammatory bowel disease. A current grand challenge in the microbiome field is to identify products produced by microbiome bacteria that tip this health-to-disease balance. The lack of knowledge about these products is a significant barrier to improving therapies that modulate our microbiome (e.g. fecal transplants)—a current area of intense investigation. The objective of my laboratory is to identify products from normal microbiome bacteria that promote health or disease and determine their mechanisms of action. To this end, we discovered a previously undescribed family of Contractile Injection System that bacteria use to naturally promote the development of an invertebrate host (a tubeworm called Hydroides elegans). Contractile Injection Systems work by injecting stimulatory effector proteins into host cells that either promote development or elicit disease. This new family of Contractile Injection System is unique because they exclusively target eukaryotic organisms (e.g. amoeba, insects, tubeworms). Until now, this family of Injection System was not known to occur in human-associated bacteria. However, we recently discovered that the gut microbiomes of nearly all human adults (>99%) from the United States and Europe carry a closely related, yet previously undescribed Contractile Injection System. Moreover, our in vitro experiments show that Contractile Injection Systems in Bacteroides bacteria promote human cell line proliferation and inflammatory responses. In this proposal, we will lay the foundation for determining the impact of these newly discovered Contractile Injection Systems on human health. Our central hypothesis that this new Injection System family comprise a key means of interaction between microbiome bacteria and host, promoting both development and disease depending on the effectors deployed and context of interaction. Efforts for the next five years focus on (Project 1) investigating the functions of Subtype-4 CIS effector proteins and link effector activity with the host’s cellular responses; (Project 2) determining how this class of CIS binds to eukaryotic cells using fibers that structurally resemble eukaryotic cadherin proteins; and (Project 3) elucidating the structure-function relationship of Subtype-4 CIS from human gut Bacteroidales using cryo- electron tomography and fluorescence microscopy. Our results will lay a foundation for technology employing Bacteroidales bacteria and their Contractile Injection Systems as probiotics to modulate the human microbiome and host health.

项目摘要 人体微生物组中的细菌通常有益于宿主。然而，一些国家的不平衡 细菌群如类杆菌可导致肥胖和肠道炎症等疾病 疾病微生物组领域目前面临的一个重大挑战是识别由微生物组产生的产品。 微生物群细菌打破了这种健康与疾病的平衡。对这些知识的缺乏 产品是改善调节我们的微生物组（例如粪便微生物）的疗法的重大障碍。 移植）-目前正在深入研究的领域。我实验室的目标是 来自正常微生物组细菌的产品，促进健康或疾病，并确定其 行动机制。为此，我们发现了一个以前未描述的收缩家族， 细菌用来自然促进无脊椎动物宿主发育的注射系统 （一种叫做Hydroides elegans的管虫）。收缩注射系统通过注射 刺激效应蛋白进入宿主细胞，促进发育或引发疾病。这 收缩注射系统的新家族是独特的，因为它们专门针对真核生物 生物体（如变形虫、昆虫、管虫）。到目前为止，这个注射系统家族还没有 已知发生在与人类相关的细菌中。然而，我们最近发现， 来自美国和欧洲的几乎所有成年人（>99%）的微生物组都携带一种密切的 相关的，但以前未描述的收缩注射系统。此外，我们的体外 实验表明，收缩注射系统中的拟杆菌促进人体细胞 线增殖和炎症反应。在这份提案中，我们将为以下方面奠定基础 确定这些新发现的收缩注射系统对人类健康的影响。 我们的中心假设是，这种新的注射系统系列包括一种关键的相互作用方式， 微生物组细菌和宿主之间，促进发展和疾病取决于 所部署的效应器和交互的上下文。未来五年的工作重点是（项目 1)研究亚型-4 CIS效应蛋白的功能，并将效应活性与 宿主的细胞反应;（项目2）确定这类CIS如何与真核细胞结合 使用结构上类似于真核细胞钙粘蛋白的纤维;和（项目3）阐明 人肠道类杆菌4亚型CIS结构与功能关系研究 电子断层扫描和荧光显微镜。我们的成果将为技术奠定基础 使用拟杆菌目细菌及其收缩注射系统作为益生菌， 调节人体微生物组和宿主健康。

项目成果

Future research directions of the model marine tubeworm Hydroides elegans and synthesis of developmental staging of the complete life cycle

模型海洋管虫Hydrides elegans的未来研究方向及全生命周期发育阶段的综合

• DOI: 10.1002/dvdy.628
• 发表时间: 2023
• 期刊: Developmental Dynamics
• 影响因子: 2.5
• 作者: Nesbit, Katherine T.;Shikuma, Nicholas J.
• 通讯作者: Shikuma, Nicholas J.