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

Autor: McLellan LK; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America., McAllaster MR; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America., Kim AS; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America., Tóthová Ľ; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America., Olson PD; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America.; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America., Pinkner JS; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America., Daugherty AL; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America., Hreha TN; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America., Janetka JW; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, United States of America., Fremont DH; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, United States of America., Hultgren SJ; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America., Virgin HW; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America., Hunstad DA; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America.; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2021 Jan 29; Vol. 17 (1), pp. e1009314. Date of Electronic Publication: 2021 Jan 29 (Print Publication: 2021).
DOI: 10.1371/journal.ppat.1009314
Abstrakt: 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.
Databáze: MEDLINE
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