The Pathogenic Potential of Proteus mirabilis Is Enhanced by Other Uropathogens during Polymicrobial Urinary Tract Infection

Abstract

Urinary catheter use is prevalent in health care settings, and polymicrobial colonization by urease-positive organisms, such as Proteus mirabilis and Providencia stuartii, commonly occurs with long-term catheterization. We previously demonstrated that coinfection with P. mirabilis and P. stuartii increased overall urease activity in vitro and disease severity in a model of urinary tract infection (UTI). In this study, we expanded these findings to a murine model of catheter-associated UTI (CAUTI), delineated the contribution of enhanced urease activity to coinfection pathogenesis, and screened for enhanced urease activity with other common CAUTI pathogens. In the UTI model, mice coinfected with the two species exhibited higher urine pH values, urolithiasis, bacteremia, and more pronounced tissue damage and inflammation compared to the findings for mice infected with a single species, despite having a similar bacterial burden within the urinary tract. The presence of P. stuartii, regardless of urease production by this organism, was sufficient to enhance P. mirabilis urease activity and increase disease severity, and enhanced urease activity was the predominant factor driving tissue damage and the dissemination of both organisms to the bloodstream during coinfection. These findings were largely recapitulated in the CAUTI model. Other uropathogens also enhanced P. mirabilis urease activity in vitro, including recent clinical isolates of Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, and Pseudomonas aeruginosa. We therefore conclude that the underlying mechanism of enhanced urease activity may represent a widespread target for limiting the detrimental consequences of polymicrobial catheter colonization, particularly by P. mirabilis and other urease-positive bacteria.KEYWORDS CAUTI, Enterococcus, Proteus mirabilis, Providencia stuartii, UTI, catheterassociated urinary tract infection, polymicrobial, urease, urinary tract infection U rinary catheters are common in health care settings and are utilized by over 60% of critically ill patients, 20% of patients in medical and surgical units, and 5 to 10% of residents in nursing homes (1-3). The incidence of bacteria in urine (bacteriuria) is 3 to 8% per day of catheterization, and long-term catheterization (Ͼ30 days) results in continuous bacteriuria (1). The microbial composition of urine colonization changes over time, initially involving Escherichia coli, Klebsiella pneumoniae, Serratia spp., Citrobacter spp., Enterobacter spp., Pseudomonas aeruginosa, and/or Gram-positive cocci and

Network of microbial and antibiotic interactions drive colonization and infection with multidrug-resistant organisms

“…P. mirabilis is known for its propensity to produce both monospecies and polymicrobial biofilms, commonly with urease-producing species (33,34). Although MRSA is the only species in our culture collection that has been characterized as a urease producer (35), a recent study showed that P. mirabilis urease production is enhanced in the presence of urease nonproducers, including Enterococcus, A. baumannii, and E. coli (36). Thus, communication among MDROs, whether dependent on chemical signaling or physical contact, may underlie the associations among these organisms.…”

Pathogenesis of Proteus mirabilis Infection

“…All of these potential complications of catheter insertion provide P. mirabilis with additional sites of attachment, nutrients, and routes for establishing more severe infection. The presence of an indwelling urinary catheter also elicits a robust inflammatory response, both in humans and in experimental animal models, and the resulting accumulation of fibrinogen on the catheter surface can provide bacteria with an ideal substrate for attachment (23–25). …”

“…Because P. mirabilis is often part of a polymicrobial infection, the impact of polymicrobial colonization on urease activity and urolithiasis in a murine CAUTI model has been examined for coinfection of P. mirabilis and its common CAUTI partner Providencia stuartii (25, 41). Coinfection resulted in bacterial loads that were similar to monoinfections with either pathogen.…”

“…Bladder colonization by P. mirabilis most often results in mild to moderate cystitis in murine models of UTI, including transmural neutrophilic inflammation, epithelial transcytosis of neutrophils, and submucosal edema (25, 55). The pathology of P. mirabilis bladder colonization during ascending UTI is largely due to a combination of urease activity, Pta, and hemolysin (25, 55).…”

Contactless Ammonia Mapping for Concentric Colony Pattern of <i>Proteus mirabilis</i>

“…Together with other bacteria, Proteus mirabilis is known as urinary tract infection (UTI) bacteria and the coinfection is reported to increase overall urease activity in vitro and disease severity in UTI (Armbruster et al, 2017). The bacteria form crystalline biofilms on the catheters surface, which is highly tolerant to antibiotics (Melo et al, 2016).…”