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

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. He...

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Veröffentlicht in:PLoS pathogens 2021-01, Vol.17 (1), p.e1009314-e1009314
Hauptverfasser: McLellan, Lisa K, McAllaster, Michael R, Kim, Arthur S, Tóthová, Ľubomíra, Olson, Patrick D, Pinkner, Jerome S, Daugherty, Allyssa L, Hreha, Teri N, Janetka, James W, Fremont, Daved H, Hultgren, Scott J, Virgin, Herbert W, Hunstad, David A
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container_start_page e1009314
container_title PLoS pathogens
container_volume 17
creator McLellan, Lisa K
McAllaster, Michael R
Kim, Arthur S
Tóthová, Ľubomíra
Olson, Patrick D
Pinkner, Jerome S
Daugherty, Allyssa L
Hreha, Teri N
Janetka, James W
Fremont, Daved H
Hultgren, Scott J
Virgin, Herbert W
Hunstad, David A
description 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.
doi_str_mv 10.1371/journal.ppat.1009314
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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. 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ispartof PLoS pathogens, 2021-01, Vol.17 (1), p.e1009314-e1009314
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1553-7366
1553-7374
language eng
recordid cdi_plos_journals_2490315603
source MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central Open Access; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects Abscesses
Adhesins, Escherichia coli - genetics
Adhesins, Escherichia coli - metabolism
Animals
Binding
Biology and Life Sciences
Bladder
Catheters
Collecting duct
Desmoglein 2 - genetics
Desmoglein 2 - metabolism
Ducts
E coli
Epithelium
Epithelium - microbiology
Escherichia coli
Escherichia coli - genetics
Escherichia coli - pathogenicity
Escherichia coli Infections - microbiology
Female
Females
Fimbriae Proteins - genetics
Fimbriae Proteins - metabolism
Fimbriae, Bacterial - genetics
Fimbriae, Bacterial - metabolism
Genetic aspects
Humans
Infection
Kidneys
Lectins
Localization
Male
Males
Medicine and Health Sciences
Mice
Mice, Inbred C3H
Microscopy
Pathogenesis
Pathogens
Pili
Pyelonephritis
Pyelonephritis - microbiology
Research and Analysis Methods
Urinary Bladder - microbiology
Urinary tract infections
Urogenital system
Virulence
title A host receptor enables type 1 pilus-mediated pathogenesis of Escherichia coli pyelonephritis
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