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An In Vitro Bladder Model of Catheter-Associated Urinary Tract Infection
Published on: June 24, 2025
MrpJ Directly Regulates Proteus mirabilis Virulence Factors, Including Fimbriae and Type VI Secretion, during Urinary
Irina Debnath1, Anne M Stringer2, Sara N Smith3
1Department of Microbiology, New York University Medical Center, New York, New York, USA.
Abstract:
Proteus mirabilis is a leading cause of catheter-associated urinary tract infections (CAUTIs) and urolithiasis. The transcriptional regulator MrpJ inversely modulates two critical aspects of P. mirabilis UTI progression: fimbria-mediated attachment and flagellum-mediated motility. Transcriptome data indicated a network of virulence-associated genes under MrpJ's control. Here, we identify the direct gene regulon of MrpJ and its contribution to P. mirabilis pathogenesis, leading to the discovery of novel virulence targets. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) was used for the first time in a CAUTI pathogen to probe for in vivo direct targets of MrpJ. Selected MrpJ-regulated genes were mutated and assessed for their contribution to UTI using a mouse model. ChIP-seq revealed a palindromic MrpJ binding sequence and 78 MrpJ-bound regions, including binding sites upstream of genes involved in motility, fimbriae, and a type VI secretion system (T6SS). A combinatorial mutation approach established the contribution of three fimbriae (fim8A, fim14A, and pmpA) to UTI and a new pathogenic role for the T6SS in UTI progression. In conclusion, this study (i) establishes the direct gene regulon and an MrpJ consensus binding site and (ii) led to the discovery of new virulence genes in P. mirabilis UTI, which could be targeted for therapeutic intervention of CAUTI.
Insights
Proteus mirabilis uses the regulator MrpJ to control attachment and motility during urinary tract infections (UTIs). This study identified MrpJ's direct targets, revealing new virulence factors like the type VI secretion system (T6SS) for potential therapeutic strategies against UTIs.
Area of Science:
- Microbiology
- Infectious Diseases
- Molecular Biology
Background:
- Proteus mirabilis is a primary cause of catheter-associated urinary tract infections (CAUTIs) and kidney stones.
- The transcriptional regulator MrpJ influences P. mirabilis's ability to attach and move, key factors in UTI development.
Purpose of the Study:
- To identify the direct genes regulated by MrpJ.
- To understand MrpJ's role in P. mirabilis pathogenesis.
- To discover novel virulence targets for therapeutic intervention.
Main Methods:
- Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) was employed to map MrpJ binding sites.
- Gene mutations were created to assess the contribution of MrpJ-regulated genes to UTI progression in a mouse model.
Main Results:
- ChIP-seq identified 78 MrpJ binding regions and a consensus binding sequence.
- Key genes regulated by MrpJ include those involved in motility, fimbriae (fim8A, fim14A, pmpA), and a type VI secretion system (T6SS).
- The study confirmed the role of three fimbriae in UTI and identified a novel pathogenic role for the T6SS.
Conclusions:
- This research defines the direct regulon of MrpJ and its binding motif.
- New virulence factors in P. mirabilis, including the T6SS, were discovered, offering potential targets for novel CAUTI therapies.
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