Positively selected FimH residues enhance virulence during urinary tract infection by altering FimH conformation

Drew J. Schwartz, Vasilios Kalas, Jerome S. Pinkner, Swaine L. Chen, Caitlin N. Spaulding, Karen W. Dodson, Scott J. Hultgren

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Chaperone-usher pathway pili are a widespread family of extracellular, Gram-negative bacterial fibers with important roles in bacterial pathogenesis. Type 1 pili are important virulence factors in uropathogenic Escherichia coli (UPEC), which cause the majority of urinary tract infections (UTI). FimH, the type 1 adhesin, binds mannosylated glycoproteins on the surface of human and murine bladder cells, facilitating bacterial colonization, invasion, and formation of biofilm-like intracellular bacterial communities. The mannose-binding pocket of FimH is invariant among UPEC. We discovered that pathoadaptive alleles of FimH with variant residues outside the binding pocket affect FimH-mediated acute and chronic pathogenesis of two commonly studied UPEC strains, UTI89 and CFT073. In vitro binding studies revealed that, whereas all pathoadaptive variants tested displayed the same high affinity for mannose when bound by the chaperone FimC, affinities varied when FimH was incorporated into pilus tip-like, FimCGH complexes. Structural studies have shown that FimH adopts an elongated conformation when complexed with FimC, but, when incorporated into the pilus tip, FimH can adopt a compact conformation. We hypothesize that the propensity of FimH to adopt the elongated conformation in the tip corresponds to its mannose binding affinity. Interestingly, FimH variants, which maintain a high-affinity conformation in the FimCGH tip-like structure, were attenuated during chronic bladder infection, implying that FimH's ability to switch between conformations is important in pathogenesis. Our studies argue that positively selected residues modulate fitness during UTI by affecting FimH conformation and function, providing an example of evolutionary tuning of structural dynamics impacting in vivo survival.

Original languageEnglish
Pages (from-to)15530-15537
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number39
DOIs
StatePublished - Sep 24 2013

Keywords

  • Chronic cystitis
  • Microbial pathogenesis
  • Protein conformations
  • Protein dynamics

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