A host receptor enables type 1 pilus-mediated pathogenesis of Escherichia coli pyelonephritis

Abstract

Type 1 pili have long been considered the major virulence factor enabling colonization of the urinary bladder by uropathogenic Escherichia coli (UPEC). The molecular pathogenesis of pyelonephritis is less well characterized, due to previous limitations in preclinical modeling of kidney infection. Here, we demonstrate in a recently developed mouse model that beyond bladder infection, type 1 pili also are critical for establishment of ascending pyelonephritis. Bacterial mutants lacking the type 1 pilus adhesin (FimH) were unable to establish kidney infection in male C3H/HeN mice. We developed an in vitro model of FimH-dependent UPEC binding to renal collecting duct cells, and performed a CRISPR screen in these cells, identifying desmoglein-2 as a primary renal epithelial receptor for FimH. The mannosylated extracellular domain of human DSG2 bound directly to the lectin domain of FimH in vitro, and introduction of a mutation in the FimH mannose-binding pocket abolished binding to DSG2. In infected C3H/HeN mice, type 1-piliated UPEC and Dsg2 were co-localized within collecting ducts, and administration of mannoside FIM1033, a potent small-molecule inhibitor of FimH, significantly attenuated bacterial loads in pyelonephritis. Our results broaden the biological importance of FimH, specify the first renal FimH receptor, and indicate that FimH-targeted therapeutics will also have application in pyelonephritis.

High mannose level in bladder cancer enhances type 1 fimbria–mediated attachment of uropathogenic E. coli

“…Due to its mannose-specific binding ( McLellan et al., 2021 ; Mohammad Zadeh et al., 2021 ), we used type 1 fimbria expressing UPEC to confirm higher mannose levels in human bladder cancer tissue, compared to non-cancerous bladder uroepithelium. Attachment of GFP-expressing Fim ON to human tumor or normal bladder tissue was monitored in the absence or presence of soluble mannose, galactose ( Figure 2D ), or ConA ( Figure 2E ).…”

Polysaccharides from Vaccaria segetalis seeds reduce urinary tract infections by inhibiting the adhesion and invasion abilities of uropathogenic Escherichia coli

“…These adhesins interact with different receptors (α-D-mannosylated proteins, glycosphingolipids, neuraminic acids, lactosylceramides, decay-accelerating factors, and matrix proteins) located on the urethral cell membrane ( Antaão et al., 2009 ; Lüthje and Brauner, 2014 ; Luna-Pineda et al., 2019 ). The recombinases (fimH, fimA, fimB, fimE) of UPEC type I fimbriae interact with uroplakins and other host proteins that contain mannosidaes, leading to an infiltration process that allows UPEC to avoid the flow of urine, antibodies in urine, bactericidal molecules, and antibiotic activity ( Mulvey et al., 1998 ; McLellan et al., 2021 ). The P fimbriae of UPEC enable colonization and inflammatory responses by binding papG adhesion to glycolipids and TLR4 in host cells ( Fischer et al., 2006 ; Huang et al., 2020 ; Lane et al., 2007a ).…”

Identification of Desmoglein-2 as a novel target of Helicobacter pylori HtrA in epithelial cells

“…Bacterial pathogenesis induced by pathogenic Escherichia coli (EPEC, EHEC, or UPEC) pathovars can be influenced by hDsg2 as well. The type 1 pilus adhesin (FimH) expressed by UPEC binds hDsg2 to establish kidney infection in male C3H/HeN mice [ 43 ]. EPEC disrupts desmosomes, weakens cell–cell adhesion and perturbs barrier function of intestinal epithelial cells, which involves a cellular redistribution of hDsg2 during infection [ 44 ].…”