title: Differential stability and trade-off effects of pathoadaptive mutations in the Escherichia coli FimH adhesin.
abstract: FimH is the tip adhesin of mannose-specific type 1 fimbriae of Escherichia coli, which are critical to the pathogenesis of urinary tract infections. Point FimH mutations increasing monomannose (1M)-specific uroepithelial adhesion are commonly found in uropathogenic strains of E. coli. Here, we demonstrate the emergence of a mixed population of clonally identical E. coli strains in the urine of a patient with acute cystitis, where half of the isolates carried a glycine-to-arginine substitution at position 66 of the mature FimH. The R66 mutation induced an unusually strong 1M-binding phenotype and a 20-fold advantage in mouse bladder colonization. However, E. coli strains carrying FimH-R66, but not the parental FimH-G66, had disappeared from the patient's rectal and urine samples collected from 29 to 44 days later, demonstrating within-host instability of the R66 mutation. No FimH variants with R66 were identified in a large (>600 strains) sequence database of fimH-positive E. coli strains. However, several strains carrying genes encoding FimH with either S66 or C66 mutations appeared to be relatively stable in the E. coli population. Relative to FimH-R66, the FimH-S66 and FimH-C66 variants mediated only moderate increases in 1M binding but preserved the ability to enhance binding under flow-induced shear conditions. In contrast, FimH-R66 completely lost shear-enhanced binding properties, with bacterial adhesion being inhibited by shear forces and lacking a rolling mode of binding. These functional trade-offs may determine the natural populational instability of this mutation or other pathoadaptive FimH mutations that confer dramatic increases in 1M binding strength.
authors.affiliation: Department of Microbiology, University of Washington School of Medicine, 1959 North Pacific Street, Seattle, WA 98195, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Weissman
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Beskhlebnaya
authors.forename: Veronika
authors.initials: V
authors.lastname: Chesnokova
authors.forename: Sujay
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Walter E
authors.initials: WE
authors.lastname: Stamm
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hooton
authors.forename: Evgeni V
authors.initials: EV
authors.lastname: Sokurenko
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D018830:Adhesins, Escherichia coli / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001422:Bacterial Adhesion; D001483:Base Sequence; D003556:Cystitis / Q000382:microbiology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000382:microbiology; D036781:Fimbriae Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008358:Mannose / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D013314:Stress, Mechanical; D014552:Urinary Tract Infections / Q000382:microbiology*
chemical_list: D018830:Adhesins, Escherichia coli; C058769:fimH protein, E coli; D036781:Fimbriae Proteins; D008358:Mannose