Establishment of an aqueous environment as a novel mechanism of bacterial pathogenesis

建立水环境作为细菌发病机制的新机制

• 批准号: 10293988
• 负责人: SHENG YANG HE
• 金额: $ 39.43万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10293988
• 关键词: 26S proteasome; ADP-Ribosylation Factors; Affect; Air; Animals; Arabidopsis; Bacteria; Bacterial Infections; Biochemical Genetics; Biochemistry; Biological; Cell membrane; Cells; Cellular biology; Communicable Diseases; Development; Dimensions; Disease; Early Endosome; Environment; Epidermis; Family; Gases; Genetic; Goals; Golgi Apparatus; Guanine Nucleotide Exchange Factors; Homeostasis; Human; Immunity; Infection; Infection Control; Innate Immune Response; Kidney; Knowledge; Laboratories; Lead; Link; Malignant Neoplasms; Mammals; Measures; Mediating; Methods; Michigan; Microbe; Modeling; Molecular Genetics; Mouse-ear Cress; Mucous body substance; Natural Immunity; Nature; Organ; Pathogenesis; Pathway interactions; Phosphorylation; Plant Leaves; Plants; Principal Investigator; Proliferating; Proteins; Pseudomonas syringae; Regulation; Research; Respiratory System; Role; Skin; Testing; Tissues; Type III Secretion System Pathway; Universities; Vesicle; Virulence; Water; Yang; aqueous; calcium-dependent protein kinase; enteropathogenic Escherichia coli; extracellular; host microbiome; host-microbe interactions; in vivo; innovation; insight; microbial; microbiome; novel; pathogen; pathogenic bacteria; prevent; ubiquitin-protein ligase; water channel

Establishment of an aqueous environment as a novel mechanism of bacterial pathogenesis PI: HE, Sheng Yang; Michigan State University Project summary Many bacterial pathogens of plants and mammals, including humans, use the highly conserved type III secretion system (T3SS) to inject “effector proteins” into the host cell as an important paradigm of pathogenesis. The long-term goal of this project is to characterize a newly discovered T3SS-mediated virulence strategy by which bacterial pathogens create an aqueous extracellular environment in host tissues. In nature, many host-pathogen and host-microbiome interactions occur in air-exposed/connected host organs/tissues (e.g., epidermis/skin and gas-exchange organs including respiratory systems and plant leaves) in which water availability is limited and/or variable. Because microbes generally require a moist/aqueous/mucous environment to survive and proliferate, it is not well understood whether microbes actively establish an infection-conducive aqueous environment in host organs. In humans, malfunction of aquaporins has been associated with infectious diseases, kidney malfunction and even cancer development and there is an emerging link between aquaporin- mediated water transport and pathogenesis of enteropathogenic Escherichia coli. However, cause-effect relationships often remain unclear. In the past 25 years, the Principal Investigator’s lab has used the model Arabidopsis thaliana – Pseudomonas syringae interaction to discover and characterize T3SS-mediated bacterial infection mechanisms. By taking advantage of the genetic tractability of Arabidopsis and a well-characterized T3SS effector repertoire in P. syringae, the PI’s lab recently discovered a critical role of an aqueous environment in bacterial pathogenesis. In this application, three specific aims are proposed to test the central hypothesis that, by altering (i) ARF-GEFMIN7-dependent vesicular traffic and (ii) phosphorylation of aquaporins involved in regulating water transport across host plasma membrane, P. syringae disrupts water homeostasis across the host plasma membrane, resulting in an aqueous extracellular environment as an important mechanism of pathogenesis. Aim 1 will determine the role of ARF-GEFMIN7-associated host proteins in regulating vesicular traffic of aquaporins and extracellular water. Aim 2 will investigate how P. syringae T3SS effector proteins target ARF-GEFMIN7- associated vesicle traffic and aquaporins to induce an aqueous extracellular environment. Aim 3 will elucidate how activation of host immunity prevents the virulence actions of P. syringae T3SS effectors as a novel dimension of the host innate immune response. Contemporary methods in molecular genetics, cell biology, biochemistry and microbial pathogenesis will be used in this study. Successful completion of this research will significantly advance our understanding of a newly discovered bacterial virulence mechanism and its interplay with host innate immunity. As many host-microbe interactions occurs in air-connected host organs/tissues, in which water availability is restricted, it is hoped that this original research will stimulate studies to broadly examine water regulation in other host-pathogen interactions, and, in the long- term, facilitate the development of innovative and broadly applicable measures for controlling infectious diseases in diverse eukaryotic hosts, including plants, animals and humans.

水环境作为细菌致病新机制的建立