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Virulence regulation by BadR in the Lyme disease spirochete

BadR 对莱姆病螺旋体的毒力调节

基本信息

批准号：
10571907
负责人：
Zhiming Ouyang
金额：
$ 37.38万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-24 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571907
关键词：
Address Arthropods Bacteria Bacteria sigma factor KatF protein Binding Biochemical Biological Borrelia burgdorferi Borrelia oxidative stress regulator Candidate Disease Gene Chromosomes Complex Coupled Data Defect Development Disease Disparate Etiology Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Goals Growth Homologous Gene In Vitro Infection Intervention Ixodes Knowledge Life Cycle Stages Location Lyme Disease Maintenance Mammals Mediating Modality Molecular Mus Nature Operon Order Spirochaetales Pathogenicity Pathway interactions Phase Phenotype Plasmids Play Promoter Regions Proteins Proteome Regulation Regulatory Pathway Regulon Repression Role Ticks United States Vector-transmitted infectious disease Virulence Work antimicrobial arthropod-borne bacterial fitness cohort disorder prevention enhancer binding protein environmental adaptation enzootic expectation imaging approach in vivo innovation metabolome mutant novel novel vaccines outer surface lipoprotein posttranscriptional prevent trait transcriptome transcriptome sequencing transcriptomics transmission process vector vector tick virulence gene

项目摘要

ABSTRACT Borrelia burgdorferi (Bb), the etiological agent of Lyme disease, maintains itself in nature via a complex life cycle involving an arthropod (tick) vector and small mammals. During its cycle between ticks and mammals, Bb undergoes dramatic adaptive changes in order to interact with and adapt to these two disparate niches. Previously, we found that BadR, a homologue of ROK repressors, binds to the rpoS promoter region and represses the expression of rpoS. Moreover, our preliminary findings have suggested that BadR has much broader biological relevance to the life cycle of Bb other than repressing rpoS expression. First, BadR is required for Bb's optimal growth. Second, BadR plays a vital role in the establishment of mammalian infection. Contrary to the wild-type strain, a badR deletion mutant is incapable of infecting mice, suggesting that BadR governs expression of key effector proteins associated with Bb's survival in the host. Phenotypic defects of the badR mutant in mice infection are NOT related to the well documented RpoN-RpoS regulatory pathway, because all of BosR, Rrp2, RpoN, and RpoS are still produced in the badR mutant. In fact, our preliminary global transcriptomic analyses using RNA-seq have identified numerous BosR/RpoS-independent genes regulated by BadR. In addition, we found that badR is expressed throughout Bb's tick-mammal infectious cycle. These combined data give rise to our hypothesis that BadR is a master regulator governing Bb's host adaption and virulence expression. This hypothesis will be addressed in two Specific Aims. In Aim 1 of this proposal, we will employ global transcriptome/proteome profiling to define the entire BadR regulon under various in vitro and in vivo conditions. In Aim 2, we will select BadR-regulated genes based on our global transcriptome/proteome analyses and characterize their contributions to Bb's infectious cycle. These combined studies will (i) refine our knowledge on BadR-mediated gene regulation; (ii) provide a transformative understanding of the in vivo importance of the regulon; and (iii) identify novel virulence determinants. Resultant findings could lead to the development of new strategies to prevent and/or treat Lyme disease.

摘要