TY - JOUR
T1 - Host and bacterial proteases influence biofilm formation and virulence in a murine model of enterococcal catheter-associated urinary tract infection
AU - Xu, Wei
AU - Flores-Mireles, Ana L.
AU - Cusumano, Zachary T.
AU - Takagi, Enzo
AU - Hultgren, Scott J.
AU - Caparon, Michael G.
N1 - Funding Information:
We thank Dr. Lynn Hancock (University of Kansas) for providing the ΔGelE mutant. This work was supported by grant 1F32DK104516-01 to A.L.F.-M. and by grants R01-DK051406, R01-AI108749-01, and P50-DK0645400 to M.G.C., and S.J.H. from the National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85042194091&partnerID=8YFLogxK
U2 - 10.1038/s41522-017-0036-z
DO - 10.1038/s41522-017-0036-z
M3 - Article
C2 - 29134108
AN - SCOPUS:85042194091
SN - 2055-5008
VL - 3
JO - npj Biofilms and Microbiomes
JF - npj Biofilms and Microbiomes
IS - 1
M1 - 28
ER -