Mechanoregulation of EHEC virulence

EHEC毒力的机械调节

• 批准号: 9906845
• 负责人: Anne-Marie Krachler
• 金额: $ 45.6万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-02 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906845
• 关键词: Adhesions; Affect; Anti-Infective Agents; Architecture; Bacteria; Bacterial Genes; Biochemical; Cells; Chemicals; Clinical; Cues; Development; Diarrhea; Disease; Dose; Enterocolitis; Enterocytes; Environment; Escherichia coli EHEC; Exposure to; Feedback; Fishes; Gastrointestinal tract structure; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Hemolytic-Uremic Syndrome; Human; Infection; Ingestion; Intestines; Knowledge; Lead; Life Style; Liquid substance; Mechanical Stress; Mechanics; Membrane; Microbiology; Microfluidic Microchips; Modality; Modeling; Molecular; Mus; Numbness; Operon; Optics; Organism; Pathway interactions; Physiological; Physiology; Play; Process; Production; Prokaryotic Cells; Property; Regulator Genes; Research; Role; Sensory; Shiga-Like Toxins; Shock; Signal Transduction; Site; Smell Perception; Stimulus; Stress; System; Taste Perception; Testing; Touch sensation; Transcript; Transcription Coactivator; Translating; Type III Secretion System Pathway; Variant; Virulence; Virulence Factors; Vision; Vomiting; Work; Zebrafish; base; fighting; fluid flow; gene induction; gut colonization; host colonization; human pathogen; imaging approach; in vivo; insight; mechanical force; mechanotransduction; microbial; mutant; novel; pathogen; pathogenic bacteria; physical process; preference; pressure; promoter; response; shear stress; sound; temporal measurement; tissue tropism; transcriptome sequencing

PROJECT SUMMARY Environmental sensing is at the basis of an organism’s ability to adapt its physiology to respond to changes in its niche. Over the past years, it has emerged that bacteria not only perceive and respond to chemical stimuli, but are capable of sensing and processing physical forces as an environmental cue. In the case of bacterial pathogens, we and others have shown that mechanical stimuli can act as a hallmark of host colonization and lead to activation of virulence genes. Despite this realisation, our mechanistic understanding of pathways and systems involved in mechanosensing, transduction and processing of physical forces is currently limited, as is our knowledge regarding the role of mechanoregulation within the host environment. The objective here is to understand how enterohemorrhagic E. coli, an important human pathogen, responds to physical force. In the human host, ingestion of EHEC can lead to enterocolitis and severe complications such as haemolytic uremic syndrome. These hallmarks of infection are caused by the concerted action of virulence factors, including colonization factors and Shiga-like toxins. Here, we will (a) characterize how virulence gene induction responds to physical forces, (b) determine the biochemical basis of signal transduction between membrane and transcriptional regulator, and (c) define the role of mechanosensing during the transitions between environmental and host-associated lifestyles. This work will reveal how EHEC perceive and process physical forces, and integrate these cues to coordinate their infection cycle. Such knowledge may highlight new targets for the development of anti-infective strategies that disable the pathogen by rendering it ‘numb’ to the host.

项目总结 环境感知是生物体适应生理变化的能力的基础 这是它的利基市场。在过去的几年里，已经发现细菌不仅能感知化学刺激并对其做出反应， 但能够感知和处理身体力量作为环境线索。在细菌的情况下 病原体，我们和其他人已经证明，机械刺激可以作为宿主定植和 导致毒力基因的激活。尽管我们意识到了这一点，我们对路径和 目前，涉及机械感应、传递和处理物理力的系统有限。 我们对宿主环境中机械调节作用的了解。这里的目标是 了解肠出血性大肠杆菌，一种重要的人类病原体，如何对物理力量做出反应。在 人类宿主，摄入EHEC可导致小肠结肠炎和严重并发症，如溶血性尿毒症 综合症。这些感染的特征是由毒力因素的协同作用引起的，包括 定植因子与志贺样毒素。在这里，我们将(A)描述毒力基因诱导是如何响应的 对于物理作用力，(B)确定膜和膜之间信号转导的生化基础 转录调节因子，以及(C)定义了机械感知在环境和环境之间的转换中的作用 以及与宿主相关的生活方式。这项工作将揭示EHEC如何感知和处理物理力，以及 整合这些线索以协调它们的感染周期。这样的知识可能会突出新的目标 开发抗感染策略，通过使病原体对宿主变得“麻木”来禁用病原体。