Proteus mirabilis and Urinary Tract Infections
- Authors: Jessica N. Schaffer1, Melanie M. Pearson2
- Editors: Matthew A. Mulvey3, Ann E. Stapleton4, David J. Klumpp5
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VIEW AFFILIATIONS HIDE AFFILIATIONSAffiliations: 1: Department of Microbiology, New York University Langone Medical Center, New York, NY 10016; 2: Department of Microbiology, New York University Langone Medical Center, New York, NY 10016; 3: University of Utah, Salt Lake City, UT; 4: University of Washington, Seattle, WA; 5: Northwestern University, Chicago, IL
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Received 03 April 2013 Accepted 29 July 2014 Published 18 September 2015
- Correspondence: Melanie M. Pearson, [email protected]

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Abstract:
Proteus mirabilis is a Gram-negative bacterium and is well known for its ability to robustly swarm across surfaces in a striking bulls’-eye pattern. Clinically, this organism is most frequently a pathogen of the urinary tract, particularly in patients undergoing long-term catheterization. This review covers P. mirabilis with a focus on urinary tract infections (UTI), including disease models, vaccine development efforts, and clinical perspectives. Flagella-mediated motility, both swimming and swarming, is a central facet of this organism. The regulation of this complex process and its contribution to virulence is discussed, along with the type VI-secretion system-dependent intra-strain competition, which occurs during swarming. P. mirabilis uses a diverse set of virulence factors to access and colonize the host urinary tract, including urease and stone formation, fimbriae and other adhesins, iron and zinc acquisition, proteases and toxins, biofilm formation, and regulation of pathogenesis. While significant advances in this field have been made, challenges remain to combatting complicated UTI and deciphering P. mirabilis pathogenesis.
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Citation: Schaffer J, Pearson M. 2015. Proteus mirabilis and Urinary Tract Infections. Microbiol Spectrum 3(5):UTI-0017-2013. doi:10.1128/microbiolspec.UTI-0017-2013.




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Abstract:
Proteus mirabilis is a Gram-negative bacterium and is well known for its ability to robustly swarm across surfaces in a striking bulls’-eye pattern. Clinically, this organism is most frequently a pathogen of the urinary tract, particularly in patients undergoing long-term catheterization. This review covers P. mirabilis with a focus on urinary tract infections (UTI), including disease models, vaccine development efforts, and clinical perspectives. Flagella-mediated motility, both swimming and swarming, is a central facet of this organism. The regulation of this complex process and its contribution to virulence is discussed, along with the type VI-secretion system-dependent intra-strain competition, which occurs during swarming. P. mirabilis uses a diverse set of virulence factors to access and colonize the host urinary tract, including urease and stone formation, fimbriae and other adhesins, iron and zinc acquisition, proteases and toxins, biofilm formation, and regulation of pathogenesis. While significant advances in this field have been made, challenges remain to combatting complicated UTI and deciphering P. mirabilis pathogenesis.

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Figures

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FIGURE 1
P. mirabilis in urease-induced bladder stone. A, One-quarter bladder of experimentally infected mouse (bar, 500 μm). B, Higher magnification of the area indicated in panel A (bar, 100 μm). C, Higher magnification of the area indicated in panel B with individual bacteria visible (bar, 5 μm). Modified from Infect Immun ( 32 ), with permission.

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FIGURE 2
Adherence and motility genes are inversely regulated during UTI. Each line represents fold-change of a specific flagellar (left panel) or fimbrial (right panel) gene in vivo relative to mid-logarithmic phase culture in vitro. Genes in the mrp operon are highly induced early during infection, but expression falls by 7 days post infection. Flagellar genes are initially repressed, but expression increases late in infection. Modified from Infect Immun ( 25 ), with permission.

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FIGURE 3
Swarming colony of P. mirabilis.

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FIGURE 4
P. mirabilis switches between swimming and swarming forms. On the left is a transmission electron micrograph (TEM) of broth-cultured, vegetative cells displaying peritrichous flagella. On the right is a TEM of differentiated swarm cells. Bundles of flagella are visible.

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FIGURE 5
P. mirabilis swarms across sections of latex catheter. Reproduced from Infect Immun ( 61 ), with permission.

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FIGURE 6
Expression of MR/P fimbriae is phase-variable and induced during UTI. A, Immunogold electron microscopy of wild-type P. mirabilis HI4320 labeled with gold particles targeting the MrpH tip adhesin. The cell on the left is expressing MR/P fimbriae, and the cell on the right is not (bar, 500 nm). B, The amount of MR/P fimbriae present positively correlates with murine bladder colonization. Data were obtained seven days post-inoculation. Modified from J Bacteriol ( 166 ), with permission.

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FIGURE 7
P. mirabilis biofilm formation is MR/P-dependent. P. mirabilis bacteria expressing GFP were grown on a cover glass in urine for 7 days. The resulting biofilm was imaged with confocal microscopy, and the 30 resulting z-stacks were stitched together to form the sagittal view. Wild-type P. mirabilis forms thick, robust biofilms. P. mirabilis MR/P L-ON forms dense, but thin, biofilms while P. mirabilis MR/P L-OFF forms weak biofilms. Reprinted from Infect Immun ( 177 ), with permission.

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FIGURE 8
Overexpression of mrpJ and its paralogs results in distinct phenotypes. A, Swarming assays of P. mirabilis with an empty vector or expressing mrpJ or an mrpJ paralog. B, Gram-stained bacteria from the edge of the swarm front (bar, 50 μm). Modified from Mol Microbiol ( 162 ), with permission.

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FIGURE 9
P. mirabilis iron chelation is Nrp and proteobactin dependent. A, agar; and B, solution chrome azurol S (CAS) assays of uropathogenic E. coli CFT073 and P. mirabilis HI4320; a color change from blue to orange indicates iron chelation. In B), P. mirabilis supernatants from log-phase cultures grown in MOPS defined media either with 0.1 mM FeCl3·6H2O (black bars) or without supplementation (white bars) were concentrated 50-fold before being used in a liquid CAS assay (E. coli supernatants were not concentrated). Single P. mirabilis nrpR and pbtA mutants are not impaired in iron chelation, but the double P. mirabilis nrpR pbtA mutant is. Reprinted from Mol Microbiol ( 238 ), with permission.
Tables

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TABLE 1
Genes that contribute to swarming in P. mirabilis

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TABLE 2
The fimbriae of P. mirabilis. The name, genomic location, Greek classification, determination of virulence, and MrpJ homolog of each fimbrial operon in P. mirabilis

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TABLE 3
Iron-related genes in P. mirabilis. Iron-related genes from P. mirabilis were identified by homology to other iron-related genes. Genes identified as iron-related by homology but not identified using one of the four conditions shown were excluded. A checkmark indicates that one or more of the genes in the row were identified using the condition specified
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