Biophysical determinants of chemotaxis in Helicobacter pylori

幽门螺杆菌趋化性的生物物理决定因素

• 批准号: 10556394
• 负责人: Pushkar Prakash Lele
• 金额: $ 36.89万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556394
• 关键词: Adaptor Signaling Protein; Address; Anti-Bacterial Agents; Bacteria; Biological Assay; Biophysical Process; Biophysics; Cells; Chemicals; Chemoreceptors; Chemotaxis; Chemotaxis Inhibition; Chimeric Proteins; Coupling; Data; Detection; Development; Dose; Environment; Enzymes; Escherichia coli; Flagella; Fluorescence Resonance Energy Transfer; Goals; Habitats; Helicobacter Infections; Helicobacter pylori; Homologous Gene; Imaging Techniques; Individual; Infection; Inflammation; Knowledge; Ligands; Literature; Location; Mastigophora; Measures; Mediating; Methods; Microscopy; Modeling; Molecular; Motor; Outcome; Output; Pattern; Peptic Ulcer; Phase; Phosphotransferases; Play; Population; Prognosis; Proteins; Research; Role; Rotation; Running; Signal Transduction; Source; Standard Model; Stomach; Swimming; Techniques; Testing; Work; antibiotic resistant infections; biophysical techniques; cell motility; desensitization; experimental study; extracellular; innovation; insight; laser tweezer; malignant stomach neoplasm; migration; novel; novel strategies; optic tweezer; prevent; protein-histidine kinase; receptor; receptor function; response; simulation

Project Abstract Infections by the motile bacterial species, Helicobacter pylori, are promoted by chemotaxis, which refers to the ability to migrate towards favorable chemical environments. H. pylori infections are a major cause of peptic ulcers and gastric cancers. Yet, the biophysical mechanisms of chemotaxis in H. pylori are not understood. In the canonical chemotaxis network, chemoreceptors sense extracellular ligands and regulate the activity of a chemotaxis kinase. The kinase in turn modulates flagellar functions to bias bacterial migration. To prevent the network from desensitizing upon ligand-detection, two enzymes, CheR and CheB, continuously reset the kinase activity. Such resetting (adaptation) increases the dynamic range of ligand sensing in the network, without which the cell cannot continue migrating up or down chemical gradients. However, H. pylori lack CheR and CheB homologues. Also, the pattern of motility in H. pylori is different from the standard model, Escherichia coli, since H. pylori localize all their flagella at a single pole – individual cells swim forward (run) and backward (reverse), rather than running and tumbling as E. coli do. This subtle difference in motility is predicted to give rise to multiple chemotaxis errors in the canonical framework. Hence, current mechanistic models of chemotaxis are unable to explain biased and error-free migration in H. pylori. Without a fundamental understanding of chemotaxis in H. pylori, the development of antibacterials that target chemotaxis will likely remain limited. In the proposed work, the PI’s primary goal is to explain how the chemotaxis network modulates flagellar functions to promote chemotaxis in H. pylori. The PI’s long term goal is to use the insights from the proposed work to develop innovative methods to prevent H. pylori infections by inhibiting chemotaxis. The PI will make use of a novel technique that overcomes the status quo by allowing quantification of flagellar functions without probing individual flagellar motors. Through a combination of optical tweezers, phase microscopy, and stochastic modeling, the PI will determine how chemotaxis errors are prevented at a single cell and population level in H. pylori. The team will pioneer the development of novel assays, including a FRET assay, to experimentally measure chemotaxis signaling in H. pylori. The PI will also determine the role of key coupling proteins that have been hypothesized to play a major role in chemotaxis adaptation. In addition to establishing the biophysical principles of chemotaxis in H. pylori, the following payoffs are anticipated: 1) a paradigm will be established for understanding chemotaxis migration in other run-reversing species, 2) novel mechanisms of chemotaxis adaptation are likely to be elucidated, 3. a FRET-based assay will be developed, which will significantly boost current efforts in the field to understand chemoreceptor functions and chemotaxis signaling mechanisms in H. pylori. Successful execution of the projects will enable a major advance since chemotaxis strategies remain poorly understood in a large majority of bacterial species.

项目摘要