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Regulation of the virulence factor PlcH in Pseudomonas aeruginosa

铜绿假单胞菌毒力因子PlcH的调控

基本信息

批准号：
10884588
负责人：
MATTHEW J WARGO
金额：
$ 37.88万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-18 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10884588
关键词：
Betaine Biological Cells Choline Cystic Fibrosis Data Disease Environment Epithelial Cells Evolution Functional disorder Gene Expression Regulation Genetic Genetic Transcription Glycine Health Homeostasis Human Individual Infection Iron Knowledge Left Lung Lung infections Metabolic Pathway Metabolism Miltefosine Mission Modeling Mus Mutation Oxygen Pathogenesis Pathway interactions Persons Phospholipase C Phospholipids Pilum Play Positioning Attribute Post-Translational Regulation Process Production Pseudomonas aeruginosa Pulmonary Cystic Fibrosis Pulmonary Surfactants Regulation Regulatory Pathway Repression Research Role Severity of illness Signal Transduction Site Sphingolipids Sphingomyelinase Sphingosine Starvation System Testing Titrations Transcriptional Regulation Treatment Efficacy Type III Secretion System Pathway Type IV Secretion System Pathway United States National Institutes of Health Virulence Virulence Factors Work biochemical tools cell type detection platform dimethylglycine drug repurposing experience extracellular human disease human pathogen inorganic phosphate insight mutant novel pathogen periplasm surfactant targeted treatment therapeutic target tissue culture

项目摘要

Pseudomonas aeruginosa (Pa) is an important opportunistic human pathogen that deploys a variety of virulence factors, each playing roles in different infection sites or with different cell types. One important virulence factor of Pa is the hemolytic phospholipase C/sphingomyelinase, PlcH. plcH mutants are defective in a wide range of infection models and PlcH expression by strains has been correlated to human disease severity and differential treatment efficacy. There are three currently known inputs to PlcH expression: induction by phosphate starvation, induction by glycine betaine, and repression by low oxygen environments. While each of these regulatory paths have been described, there remain important gaps in our understanding of PlcH regulation as well as alterations in these regulatory pathways in specific disease contexts. In this proposal, we will determine the identity and mechanisms of previously unidentified transcriptional and posttranslational regulation of PlcH and determine the role of altered PlcH regulation during Pa adaptation in the lungs of people with cystic fibrosis. Despite the contribution of PlcH to Pa virulence, study of its regulation lags behind that of other virulence factors. Here we present preliminary data for novel transcriptional regulation of plcH, identification of a new post- translational PlcH regulatory step, and present changes to metabolic pathways directly upstream of plcH induction that occur within the cystic fibrosis lung. Our hypothesis is that PlcH production and export is regulated at multiple levels and that these regulatory steps work to titrate the flux of enzymatic products and to avoid damage to producing cells. We have longstanding experience with PlcH and a large experimental toolkit with which to approach its regulation. We are well positioned to understand the mechanisms behind uncharacterized PlcH regulatory pathways and to identify new regulatory inputs. We will address PlcH regulation by (i) determining the mechanisms of uncharacterized plcH transcriptional regulation and the importance of each mechanism of transcriptional induction, (ii) deciphering post-translational control mechanisms for PlcH, and (iii) examining alteration in PlcH expression by pathoadaptive mutations occurring during long term cystic fibrosis lung infections. The work proposed here will allow us to have a more complete understanding of PlcH regulation, providing biological insight and exposing potential targets for inhibition of PlcH production.

铜绿假单胞菌（Pa）是一种重要的机会性人类病原体，具有多种毒力