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

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