From Catheter to Kidney Stone: The Uropathogenic Lifestyle of Proteus mirabilis

Abstract

Proteus mirabilis is a model organism for urease-producing uropathogens. These diverse bacteria cause infection stones in the urinary tract and form crystalline biofilms on indwelling urinary catheters, frequently leading to polymicrobial infection. Recent work has elucidated how P. mirabilis causes all of these disease states. Particularly exciting is the discovery that this bacterium forms large clusters in the bladder lumen that are sites for stone formation. These clusters, and other steps of infection, require two virulence factors in particular: urease and MR/P fimbriae. Highlighting the importance of MR/P fimbriae is the cotranscribed regulator, MrpJ, which globally controls virulence. Overall, P. mirabilis exhibits an extraordinary lifestyle, and further probing will answer exciting basic microbiological and clinically relevant questions.

Keywords: CAUTI; Proteus mirabilis; crystalline biofilms; fimbriae; polymicrobial infections; urease; urinary stones.

Figure 1. Lifestyle of Proteus mirabilis

P. mirabilis cells form crystalline biofilms on the surface of catheters. Once inside the bladder (0.5–6 hours post-infection[hpi]), this organism can invade into urothelial cells of the bladder. As early as 10–24 hpi, P. mirabilis forms intraluminal clusters that can extend the length of the bladder and are associated with urothelial cell destruction. Host innate immune cells such as neutrophils (blue) are recruited to the site of infection and can form NETs (neutrophil extracellular traps). Figure used with permission from Schaffer et al. [1].

Figure 2. Concepts of Proteus mirabilis Pathogenesis during Urinary Tract Infection (UTI)

Bolded classes of virulence factors have genes that are regulated by MrpJ. For more extensive information on these virulence factors, see references [21,22,99,100]. Adherence: binding catheters, host tissues, and neighboring bacteria may all contribute to disease. Adherence is mediated by chaperone-usher fimbriae and autotransporter adhesins. Urease: involved in stones, crystalline biofilms, and possibly nutrition or host sensing. Motility: P. mirabilis swarms across catheters and may ascend to the kidneys using swimming motility. Both forms of motion are mediated by flagella. Chemotaxis proteins allow the bacteria to follow chemical gradients. Metabolism: likely permits establishment of a nutritional niche, competition with other species, and response to host cues. Metal scavenging: iron and zinc uptake are essential for growth, but are sequestered by the host; therefore, specialized proteins are required for bacteria to scavenge these metals. Toxins: proteins such as HpmA and Pta may aid in nutrient accessibility, immune evasion, or provision of surfaces to colonize. Biofilm formation: Crystalline biofilms readily form on catheters, and bacterial clusters in the bladder may be a biofilm-mediated process. Immune evasion: this can include antibody and antimicrobial peptide degradation, polymyxin resistance, lipopolysaccharide (LPS) variation, and physical obstruction of phagocytosis. Virulence regulation: required to coordinate all steps of infection. MrpJ-controlled systems in this figure are bolded. Type 6 secretion system (T6SS): involved in self-recognition; unknown role during UTI.