Proteus mirabilis and Urinary Tract Infections

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.

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 with permission from Infection and Immunity, volume 70, page 392, 2002 (32).

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 seven days postinfection. Flagellar genes are initially repressed, but expression increases late in infection. Modified with permission from Infection and Immunity, volume 79, page 2625 (25).

Figure 3

Swarming colony of P. mirabilis.

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.

Figure 5

P. mirabilis swarms across sections of latex catheter. Reproduced with permission from Infection and Immunity, vol 72, page 3942 (61).

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 with permission from Journal of Bacteriology vol 191, page 1385 (166).

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 with permission from Infection and Immunity vol 72, page 7299 (177).

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. The reference bar is 50 μm. Modified with permission from Molecular Microbiology, vol 69, page 551 (162).

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 with permission from Molecular Microbiology, vol 78, page 149 (238).