Abstract
Enterococcus faecalis is a leading causative agent of catheter-associated urinary tract infection (CAUTI), the most common hospital-acquired infection. Its ability to grow and form catheter biofilm is dependent upon host fibrinogen (Fg). Examined here are how bacterial and host proteases interact with Fg and contribute to virulence. Analysis of mutants affecting the two major secreted proteases of E. faecalis OG1RF (GelE, SprE) revealed that while the loss of either had no effect on virulence in a murine CAUTI model or for formation of Fg-dependent biofilm in urine, the loss of both resulted in CAUTI attenuation and defective biofilm formation. GelE−, but not SprE− mutants, lost the ability to degrade Fg in medium, while paradoxically, both could degrade Fg in urine. The finding that SprE was activated independently of GelE in urine by a host trypsin-like protease resolved this paradox. Treatment of catheter-implanted mice with inhibitors of both host-derived and bacterial-derived proteases dramatically reduced catheter-induced inflammation, significantly inhibited dissemination from bladder to kidney and revealed an essential role for a host cysteine protease in promoting pathogenesis. These data show that both bacterial and host proteases contribute to CAUTI, that host proteases promote dissemination and suggest new strategies for therapeutic intervention.
Highlights
We examined the role of secreted proteases in the ability of E. faecalis to grow and form biofilm in an optimized model of catheter-associated urinary tract infections (CAUTI) biofilm in vitro and for biofilm formation and pathogenesis in a murine model of CAUTI
Since the data presented above show that secreted enterococcal proteases enhance CAUTI pathogenesis, we investigated whether treatment with several commonly used protease inhibitors could alter the course of pathogenesis in the murine CAUTI model
Using a combination of mutants and chemical inhibition, we show that both enterococcal and host proteases contribute to the pathogenesis of E. faecalis CAUTI
Summary
Catheter-associated infections, catheter-associated urinary tract infections (CAUTI), are the most common hospital acquired infections (HAI) worldwide and account for up to 40% of HAI in the USA.[1,2] More than 560,000 patients develop CAUTI each year, which if untreated can lead to serious complications including bacteremia and death.[3,4,5,6] Over the past few decades, Enterococcus faecalis has emerged as an important cause of CAUTI, whose treatment options are becoming increasingly limited due to its resistance to heat and aseptic solutions and its inherent and acquired resistances to multiple antibiotics, including vancomycin.[7,8] understanding the molecular mechanisms of CAUTI pathogenesis is a critical need for the development of new antibiotic-sparing therapies.One trait that has been established as important for the pathogenesis of enterococcal HAI and CAUTI is their ability to form biofilm on urinary catheters and other implantable devices.[9]. Following growth in urine, mutants that expressed either GelE or SprE demonstrated an ability to associate with Fg, as compared to the mutant that lacked both proteases (ΔGS, Fig. 4d).
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