REVIEWS Merging mythology and morphology: the multifaceted lifestyle of Proteus mirabilis Chelsie E. Armbruster and Harry L. T. Mobley Abstract | Proteus mirabilis, named for the Greek god who changed shape to avoid capture, has fascinated microbiologists for more than a century with its unique swarming differentiation, Dienes line formation and potent urease activity. Transcriptome profiling during both host infection and swarming motility, coupled with the availability of the complete genome sequence for P. mirabilis, has revealed the occurrence of interbacterial competition and killing through a type VI secretion system, and the reciprocal regulation of adhesion and motility, as well as the intimate connections between metabolism, swarming and virulence. This Review addresses some of the unique and recently described aspects of P. mirabilis biology and pathogenesis, and emphasizes the potential role of this bacterium in single- species and polymicrobial urinary tract infections. Pyelonephritis In Homer’s Odyssey, Proteus was pursued by many for bacteriuria in a given patient match the faecal isolates 9 An infection of the kidney his ability to foretell the future to anyone capable of cap- from that patient . parenchyma. turing him, but he changed shape to evade his pursuers. P. mirabilis is generally not the first organism found The name Proteus was first used in bacterial nomen- on the catheter surface, but it is common in long- Urolithiasis 10,11 The formation of calculi clature by Hauser in 1885 to describe a shape-shifting term catheterization . When P. mirabilis colonizes a 1 (stones) in the kidney, bladder bacterium isolated from putrefied meat . Proteus mirabilis, catheter, the bacterial cells develop in protected com- or urethra. a Gram-negative, dimorphic, motile member of the munities known as biofilms. The biofilms that are ini- family Enterobacteriaceae, has fascinated scientists for tially formed on catheters tend to be monomicrobial, Prostatitis more than 125 years owing to its ability to differentiate but rapidly become polymicrobial during long-term Inflammation of the prostate gland. from short rods into elongated, multinucleate swarm catheterization, with up to 72% of catheters being cells that express thousands of flagella2. Members of the colonized by two or more species12. Catheter bio- Bacteriuria genus Proteus are widely distributed in nature and can be films and urine samples taken from patients under- The presence of bacteria in the isolated from soil, stagnant water, sewage and the intesti- going long-term catheterization frequently contain urine. nal tract3. P. mirabilis is a leading agent of pyelonephritis, combinations of P. mirabilis, Morganella morganii, urolithiasis, prostatitis and catheter-associated urinary Providencia stuartii, Escherichia coli, Pseudomonas tract infections (CAUTIs) and causes approximately 3% aeruginosa and Klebsiella pneumoniae5,7,13–16. Data com- of all nosocomial infections and up to 44% of CAUTIs piled over the past 30 years reveal that, depending on in the United States4–6. the study parameters and sample population, up to 77% Department of Microbiology CAUTIs are the most common health care-associated of CAUTIs are polymicrobial, and P. mirabilis is gener- and Immunology, University infections worldwide, accounting for up to 40% of hospital- ally the most common organism isolated from these of Michigan Medical School, 7 13–18 1150 West Medical Center acquired infections . The duration of catheter­ization infections . Drive, 5641 Medical Science is the most important risk factor associated with CAUTI P. mirabilis has many virulence factors that contribute Building II, Ann Arbor, development, as roughly 10–50% of patients under­­ to the establishment of a UTI in a mouse model of infec- Michigan 48109, USA. going short-term catheterization (1–7 days) develop tion19. The bacterium expresses fimbriae, or bacterial Correspondence to H.L.T.M. only bacteriuria, whereas essentially all patients catheter- appendages tipped with adhesive proteins, that mediate e‑mail: [email protected] 8 doi:10.1038/nrmicro2890 ized for 28 days or longer develop a CAUTI . CAUTIs attachment to cells in the urinary tract and probably also Published online are thought to be caused by self-inoculation of the to the catheter. In addition, P. mirabilis produces urease, 8 October 2012 catheter; indeed, for P. mirabilis, the strains causing which hydrolyses urea to carbon dioxide and ammonia. NATURE REVIEWS | MICROBIOLOGY VOLUME 10 | NOVEMBER 2012 | 743 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Table 1 | Fimbriae of Proteus mirabilis Type of Contribution to catheter Adherence capabilities in vitro Contribution to UTI pathogenesis fimbriae colonization ATFs Possible Unknown Not associated MRK fimbriae Likely Bowman’s capsules (kidney) Kidney colonization MRP fimbriae Unknown Kidney tubular cells, and epithelial cells from Bladder and kidney colonization, and reciprocal urine regulation of motility NAFs Unknown Uroepithelial cells Unknown PMFs Unknown Uroepithelial cells Bladder colonization ATFs, ambient-temperature fimbriae; MRK, mannose-resistant Klebsiella-like; MRP, mannose-resistant Proteus-like; NAFs, non-agglutinating fimbriae; PMFs, Proteus mirabilis fimbriae; UTI, urinary tract infection. This reaction provides an abundant source of nitrogen Adherence to catheters. P. mirabilis readily colonizes the for the bacterium, but also causes the formation of crys- lumen and external surface of all current catheter types, talline biofilms that block the catheter. Furthermore, and adherence is enhanced in the presence of urine24–28. P. mirabilis can differentiate into swarm cells that con- P. mirabilis encodes 17 putative fimbrial operons, the tribute to the establishment of infection by migrating most encoded by any sequenced bacterial species20. Five along the catheter. Inside the urinary tract, the bacte- fimbrial types have been characterized and reviewed29 rium has mechanisms to scavenge nutrients and evade (TABLE 1), but little is known about the contribution of the host immune response, and is capable of reciprocal fimbriae to catheter adherence and colonization. P. mira - expression of fimbriae (for adherence) and flagella (for bilis expresses mannose-resistant Klebsiella-like (MRK) motility when it needs to ascend the urinary tract). fimbriae, a type that mediates catheter attachment by There have been many recent advances in our P. stuartii 30 and Proteus penneri 31 and might therefore understanding of P. mirabilis pathogenicity, includ- contribute to colonization by P. mirabilis. The ambient- ing the publication of the complete 4.06 Mb genome temperature fimbriae (ATFs) of P. mirabilis do not con- sequence of a CAUTI isolate (P. mirabilis str. HI4320)20, tribute to colonization of the mouse urinary tract but are the identification of novel pathogenicity factors by optimally expressed at ambient temperature and could signature-tagged mutagenesis21–23, and the elucidation of therefore influence catheter colonization32,33. the intricate connections between metabolism, swarming motility, urease activity and nitrogen availability in Swarming motility. An overview of P. mirabilis swarming the establishment and persistence of P. mirabilis UTIs. motility is presented in BOX 1. Swarming describes flagellum- This Review aims to address the most recent findings dependent movement across a surface, in contrast to concerning P. mirabilis pathogenicity and to place these swimming through liquid or soft agar. This form of findings in the context of CAUTI progression, identi- motility allows P. mirabilis to migrate across catheters, fying the stage of infection (for example, initial entry gaining entry to the urinary tract4,34,35. Swarming is to the urinary tract, ascending the tract and immune required for migration across most catheter types, as evasion) to which they contribute. non-swarming mutants traverse only hydrogel-coated Furthermore, given the growing appreciation in the latex catheters, by swimming through the water-filled field for the polymicrobial nature of many infections, it channels in the matrix36. In addition, P. mirabilis cath- is imperative to consider how knowledge gained from eter biofilms contain protruding swarm cells37. Although single-species investigations can be applied to the study the role of these biofilm-associated swarm cells is unclear, and treatment of polymicrobial infection. Although few they might seed dispersal from the catheter to the studies have addressed polymicrobial CAUTIs to date, urinary tract37. P. mirabilis is frequently isolated from these infections. Most strains of P. mirabilis are unable to differentiate It is therefore important to consider how P. mirabilis and into swarm cells in liquid medium without the addition other common causes of CAUTIs interact on catheters of a thickening agent, so it is thought that differentiation and during infections, and how these interactions influ- is triggered by surface contact or inhibition of flagellar ence the course of an infection. The final section of this rotation38. Several other factors have been implicated in Review discusses P. mirabilis pathogenicity factors in the the regulation of swarming motility (and are reviewed context of polymicrobial infection and considers ways in elsewhere39,40), including the upregulator of flagellar which this organism interacts with other uropathogens. master operon (Umo) proteins, the regulator of colanic acid capsule synthesis (Rcs) phosphorelay,