1. A host receptor enables type 1 pilus-mediated pathogenesis of Escherichia coli pyelonephritis.
- Author
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McLellan LK, McAllaster MR, Kim AS, Tóthová Ľ, Olson PD, Pinkner JS, Daugherty AL, Hreha TN, Janetka JW, Fremont DH, Hultgren SJ, Virgin HW, and Hunstad DA
- Subjects
- Adhesins, Escherichia coli genetics, Animals, Desmoglein 2 genetics, Epithelium microbiology, Escherichia coli genetics, Female, Fimbriae Proteins genetics, Fimbriae, Bacterial genetics, Fimbriae, Bacterial metabolism, Humans, Male, Mice, Mice, Inbred C3H, Urinary Bladder microbiology, Virulence, Adhesins, Escherichia coli metabolism, Desmoglein 2 metabolism, Escherichia coli pathogenicity, Escherichia coli Infections microbiology, Fimbriae Proteins metabolism, Pyelonephritis microbiology
- 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., Competing Interests: I have read the journal's policy, and the authors of this manuscript have the following competing interests: D.A.H. serves on the Board of Directors for BioVersys AG, Basel, Switzerland. J.W.J. and S.J.H. are inventors on US patent US8937167 B2, which covers the use of mannoside-based FimH ligand antagonists for the treatment of disease. J.W.J. and S.J.H. have ownership interest in Fimbrion Therapeutics. All other authors have no conflicts to declare.
- Published
- 2021
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