<i>Proteus mirabilis</i>uroepithelial cell adhesin (UCA) fimbria plays a role in the colonization of the urinary tract

Pellegrino, Rafael; Scavone, Paola; Umpiérrez, Ana; Maskell, Duncan J.; Zunino, Pablo

doi:10.1111/2049-632x.12027

Cited by 37 publications

(25 citation statements)

References 19 publications

(31 reference statements)

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“…To examine these questions, we focused on a subset of four fimbriae and associated regulators of particular interest. First, both MR/P and uroepithelial cell adhesin (UCA) have individually been shown to play a role in infection using mouse models of ascending UTI (15,16). Next, Fim8 was found to contribute to virulence in a signature-tagged mutagenesis screen (14), but this has not independently been verified.…”

Section: Resultsmentioning

confidence: 99%

“…We chose MrpJ and UcaJ for the chimeric protein approach; while MrpJ has already been established as a master regulator of virulence (24), UcaJ overproduction consistently showed a larger effect on the examined fimbrial targets, despite lacking the ability to induce its own operon. Additionally, deletion of ucaA, which likely has polar effects on ucaJ expression, attenuated P. mirabilis in a mouse model of ascending UTI (15). To assess the production of all variants, we monitored their protein levels using an epitope tag.…”

Section: Resultsmentioning

confidence: 99%

“…Four of these 17 operons have individually been linked to virulence in a murine model of infection (11)(12)(13)(14)(15)(16). Mannose-resistant Proteus-like (MR/P) fimbriae, the major adhesin produced during infection, contribute to bladder colonization (16).…”

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confidence: 99%

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Distinct Residues Contribute to Motility Repression and Autoregulation in the Proteus mirabilis Fimbria-Associated Transcriptional Regulator AtfJ

et al. 2016

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Proteus mirabilis contributes to a significant number of catheter-associated urinary tract infections, where coordinated regulation of adherence and motility is critical for ascending disease progression. Previously, the mannose-resistant Proteus-like (MR/P) fimbria-associated transcriptional regulator MrpJ has been shown to both repress motility and directly induce the transcription of its own operon; in addition, it affects the expression of a wide range of cellular processes. Interestingly, 14 additional mrpJ paralogs are included in the P. mirabilis genome. Looking at a selection of MrpJ paralogs, we discovered that these proteins, which consistently repress motility, also have nonidentical functions that include cross-regulation of fimbrial operons. A subset of paralogs, including AtfJ (encoded by the ambient temperature fimbrial operon), Fim8J, and MrpJ, are capable of autoinduction. We identified an element of the atf promoter extending from 487 to 655 nucleotides upstream of the transcriptional start site that is responsive to AtfJ, and we found that AtfJ directly binds this fragment. Mutational analysis of AtfJ revealed that its two identified functions, autoregulation and motility repression, are not invariably linked. Residues within the DNA-binding helix-turn-helix domain are required for motility repression but not necessarily autoregulation. Likewise, the C-terminal domain is dispensable for motility repression but is essential for autoregulation. Supported by a three-dimensional (3D) structural model, we hypothesize that the C-terminal domain confers unique regulatory capacities on the AtfJ family of regulators. IMPORTANCEBalancing adherence with motility is essential for uropathogens to successfully establish a foothold in their host. Proteus mirabilis uses a fimbria-associated transcriptional regulator to switch between these antagonistic processes by increasing fimbrial adherence while simultaneously downregulating flagella. The discovery of multiple related proteins, many of which also function as motility repressors, encoded in the P. mirabilis genome has raised considerable interest as to their functionality and potential redundancy in this organism. This study provides an important advance in this field by elucidating the nonidentical effects of these paralogs on a molecular level. Our mechanistic studies of one member of this group, AtfJ, shed light on how these differing functions may be conferred despite the limited sequence variety exhibited by the paralogous proteins.T ranscriptional regulation in response to environmental cues, including temperature and nutrient availability, is critical to allow bacteria to adapt to their surroundings. The advent of whole-genome sequencing has led to the discovery that some pathogenic bacteria devote as much as 10% of their genome to regulatory systems, such as transcription factors, allowing for the appropriate protective or adaptive response to new environments (1, 2).Urinary tract pathogens, such as the Gram-negative enterobacterium Proteu...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Distinct Residues Contribute to Motility Repression and Autoregulation in the Proteus mirabilis Fimbria-Associated Transcriptional Regulator AtfJ

et al. 2016

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“…Fimbrial regulation is a quintessential aspect of virulence in many pathogens, including causative agents of UTIs, and in many instances, more than one fimbrial type contributes to disease progression depending on the environmental cues or tissue niches (4,71). Although several fimbriae, including MR/P, PMF, and Fim14, have been reported to modulate P. mirabilis pathogenesis, little is known about the regulation and combinatorial implication of fimbriae in P. mirabilis-mediated UTIs (13,15,57,72). To our knowledge, this is the first report describing a molecular regulator simultaneously targeting a number of fimbriae in a positive or negative manner in this uropathogen.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Analysis of the MrpJ Network: Modulation of Diverse Virulence-Associated Genes and Direct Regulation of mrp Fimbrial and flhDC Flagellar Operons in Proteus mirabilis

et al. 2015

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The enteric bacterium Proteus mirabilis is associated with a significant number of catheter-associated urinary tract infections (UTIs). Strict regulation of the antagonistic processes of adhesion and motility, mediated by fimbriae and flagella, respectively, is essential for disease progression. Previously, the transcriptional regulator MrpJ, which is encoded by the mrp fimbrial operon, has been shown to repress both swimming and swarming motility. Here we show that MrpJ affects an array of cellular processes beyond adherence and motility. Microarray analysis found that expression of mrpJ mimicking levels observed during UTIs leads to differential expression of 217 genes related to, among other functions, bacterial virulence, type VI secretion, and metabolism. We probed the molecular mechanism of transcriptional regulation by MrpJ using transcriptional reporters and chromatin immunoprecipitation (ChIP). Binding of MrpJ to two virulence-associated target gene promoters, the promoters of the flagellar master regulator flhDC and mrp itself, appears to be affected by the condensation state of the native chromosome, although both targets share a direct MrpJ binding site proximal to the transcriptional start. Furthermore, an mrpJ deletion mutant colonized the bladders of mice at significantly lower levels in a transurethral model of infection. Additionally, we observed that mrpJ is widely conserved in a collection of recent clinical isolates. Altogether, these findings support a role of MrpJ as a global regulator of P. mirabilis virulence. Bacterial pathogens utilize a myriad of complex regulatory networks to adapt gene expression in response to environmental cues encountered in the host. Trying to walk a fine balance of avoiding detection by the host immune system, while ensuring acquisition of all essential nutrients and promoting growth, bacteria employ transcriptional and posttranscriptional strategies to combat the host's defenses. A prominent example is the specific induction of iron and zinc uptake systems during infection, regulated by Fur and Zur, respectively, which allows pathogens to gain access to these essential transition metals in the restricted host environment (1, 2).Urinary tract infections (UTIs) are among the most common bacterial infections (3), presenting a significant public health burden amounting to annual costs of about 3.5 billion dollars in the United States alone (4). Although Proteus mirabilis causes a relatively small proportion of UTIs in healthy individuals, it is a common cause of cystitis and pyelonephritis in individuals with indwelling catheters or anatomical abnormalities of the urinary tract (4, 5).UTIs occur almost exclusively in an ascending route, meaning that bacteria of fecal origin gain entry to the bladder via the urethra and then spread to the kidneys via the ureters (4). Initially, bacteria adhere to host epithelial cells via proteinaceous supramolecular structures referred to as fimbriae (or pili) (6), which allow pathogens to withstand the mechanical flow of urine (5)...

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“…Proteus mirabilis is an opportunistic pathogen that can cause severe UTIs, with serious kidney damages that could lead to death (11). Rhesus monkeys or ferrets are suitable animal models for future research on the mechanism of P. mirabilis-induced UTI and its corresponding treatment.…”

Section: Discussionmentioning

confidence: 99%

Multidrug-Resistant Proteus mirabilis Isolated From Newly Weaned Infant Rhesus Monkeys and Ferrets

Huang

2015

Jundishapur J Microbiol

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Background:Proteus mirabilis is an important uropathogen that causes complicated Urinary Tract Infection (UTI) and induces diarrhea in infants. Objectives: This study aimed to investigate P. mirabilis infection in newly weaned infant rhesus monkeys (Macaca mulatta) and ferrets (Mustela putorius furo) with diarrhea. Materials and Methods: Stool samples were collected from 74 rhesus monkeys and 12 ferrets with diarrhea. Proteus mirabilis was isolated from the samples through Polymerase Chain Reaction. The isolated P. mirabilis was subjected to antimicrobial susceptibility tests. Results: Seven (7/74, 9.5%) and four (4/12, 30%) P. mirabilis strains were detected in the stool samples collected from the monkeys and ferrets, respectively. Sequence analyses showed that the isolated P. mirabilis was closely related to P. mirabilis strain HI4320, which was isolated from the urine of a patient with a long-term indwelling urinary catheter. In addition, the isolates demonstrated multidrug resistance. Conclusions: Rhesus monkeys and ferrets are susceptible to P. mirabilis, making them useful as animal models for future studies on the mechanism of P. mirabilis-induced UTI and its corresponding treatment.

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Proteus mirabilisuroepithelial cell adhesin (UCA) fimbria plays a role in the colonization of the urinary tract

Cited by 37 publications

References 19 publications

Distinct Residues Contribute to Motility Repression and Autoregulation in the Proteus mirabilis Fimbria-Associated Transcriptional Regulator AtfJ

Distinct Residues Contribute to Motility Repression and Autoregulation in the Proteus mirabilis Fimbria-Associated Transcriptional Regulator AtfJ

Transcriptional Analysis of the MrpJ Network: Modulation of Diverse Virulence-Associated Genes and Direct Regulation of mrp Fimbrial and flhDC Flagellar Operons in Proteus mirabilis

Multidrug-Resistant Proteus mirabilis Isolated From Newly Weaned Infant Rhesus Monkeys and Ferrets

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