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Deletion of the Transcriptional Regulator MucR in Brucella canis Affects Stress Responses and Bacterial Virulence.

ABSTRACT: The transcriptional regulator MucR is related to normal growth, stress responses and Brucella virulence, and affects the expression of various virulence-related genes in smooth-type Brucella strains. However, the function of MucR in the rough-type Brucella canis remains unknown. In this study, we discovered that MucR protein was involved in resistance to heat stress, iron-limitation, and various antibiotics in B. canis. In addition, the expression level of various bacterial flagellum-related genes was altered in mucR mutant strain. Deletion of this transcriptional regulator in B. canis significantly affected Brucella virulence in RAW264.7 macrophage and mice infection model. To gain insight into the genetic basis for distinctive phenotypic properties exhibited by mucR mutant strain, RNA-seq was performed and the result showed that various genes involved in translation, ribosomal structure and biogenesis, signal transduction mechanisms, energy production, and conversion were significantly differently expressed in ΔmucR strain. Overall, these studies have not only discovered the phenotype of mucR mutant strain but also preliminarily uncovered the molecular mechanism between the transcriptional regulator MucR, stress response and bacterial virulence in B. canis.

SUBMITTER: Sun J

PROVIDER: S-EPMC8267065 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Histone-like nucleoid structuring (H-NS) and H-NS-like proteins serve as global gene silencers and work with antagonistic transcriptional activators (counter-silencers) to properly coordinate the expression of virulence genes in pathogenic bacteria. In Brucella, MucR has been proposed as a novel H-NS-like gene silencer, but direct experimental evidence is lacking. Here, we show that MucR serves as an H-NS-like silencer of the Brucella abortus genes encoding the polar autotransporter adhesins BtaE and BmaC, the c-di-GMP-specific phosphodiesterase BpdB, and the quorum-sensing regulator BabR. We also demonstrate that the MarR-type transcriptional activator MdrA can displace MucR from the btaE promoter, supporting the existence of MucR counter-silencers in Brucella. Moreover, our chromatin immunoprecipitation (ChIP)-seq analysis identified 546 MucR enrichment peaks along the genome, including in the promoters of the genes encoding the Type IV secretion machinery and effectors and the quorum-sensing regulator VjbR. Importantly, MucR ChIP-seq peaks overlap with the previously described binding sites for the transcriptional activators VjbR, BvrR, and CtrA suggesting that these regulators serve as MucR counter-silencers and work in concert with MucR to coordinate virulence gene expression in Brucella. In addition, using chromosome conformation capture (Hi-C), we show that like H-NS in Escherichia coli, MucR alters the global structure of the Brucella nucleoid. Finally, a copy of the E. coli hns rescues the distinctive growth defect and elevated btaE expression of a B. abortus mucR mutant. Together, these findings solidify the role of MucR as a novel type of H-NS-like protein and suggest that MucR's gene-silencing properties play a key role in virulence in Brucella. IMPORTANCE Histone-like nucleoid structuring (H-NS) and H-NS-like proteins coordinate host-associated behaviors in many pathogenic bacteria, often through forming silencer/counter-silencer pairs with signal-responsive transcriptional activators to tightly control gene expression. Brucella and related bacteria do not encode H-NS or homologs of known H-NS-like proteins, and it is unclear if they have other proteins that perform analogous functions during pathogenesis. In this work, we provide compelling evidence for the role of MucR as a novel H-NS-like protein in Brucella. We show that MucR possesses many of the known functions attributed to H-NS and H-NS-like proteins, including the formation of silencer/counter-silencer pairs to control virulence gene expression and global structuring of the nucleoid. These results uncover a new role for MucR as a nucleoid structuring protein and support the importance of temporal control of gene expression in Brucella and related bacteria.

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Deletion of the Transcriptional Regulator MucR in Brucella canis Affects Stress Responses and Bacterial Virulence.

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