Glycolipid depletion in antimicrobial therapy.
Mucosal pathogens target sites of infection through specific adherence to host glycoconjugate receptors. As a consequence, depletion of such receptors from the cell surface may be expected to inhibit attachment, impair bacterial colonization and reduce the activation of mucosal inflammation. We have used the glucose analogue and glycosphingolipid (GSL) biosynthesis inhibitor N-butyldeoxynojirimycin (NB-DNJ) to deplete human uroepithelial cells and the murine urinary tract mucosa of receptors for P-fimbriated Escherichia coli. NB-DNJ blocks the ceramide-specific glucosyltransferase, which catalyses the formation of glucosyl ceramide (GlcCer), the precursor for GSLs. The inhibitor was shown to decrease the GSL content in a dose-dependent way, and depletion markedly inhibited P-fimbriated bacterial attachment in vitro. NB-DNJ-fed C3H/HeN mice were depleted of GSLs in vivo and showed reduced susceptibility to experimental urinary tract infection with P-fimbriated E. coli. The mucosal inflammatory response was impaired, as shown by reduced chemokine secretion and lower neutrophil recruitment, and the bacteria colonized the urinary tract less efficiently than in normal mice. These results confirmed the role of P fimbriae-mediated adherence for colonization and inflammation and point to an interesting alternative to antibiotic treatment for urinary tract infection.
Svensson
Majlis
M
Department of Laboratory Medicine, Division of Microbiology, Lund University, S-223 62 Lund, Sweden.
Frendeus
Björn
B
Butters
Terry
T
Platt
Frances
F
Dwek
Raymond
R
Svanborg
Catharina
C
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D010861:Fimbriae, Bacterial / Q000378:metabolism; D006028:Glycosphingolipids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D011956:Receptors, Cell Surface / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology
D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D017485:1-Deoxynojirimycin; C059896:miglustat