title: Copper Is a Host Effector Mobilized to Urine during Urinary Tract Infection To Impair Bacterial Colonization.
abstract: Urinary tract infection (UTI) is a major global infectious disease affecting millions of people annually. Human urinary copper (Cu) content is elevated during UTI caused by uropathogenicEscherichia coli(UPEC). UPEC upregulates the expression of Cu efflux genes during clinical UTI in patients as an adaptive response to host-derived Cu. Whether Cu is mobilized to urine as a host response to UTI and its role in protection against UTI remain unresolved. To address these questions, we tested the hypothesis that Cu is a host effector mobilized to urine during UTI to limit bacterial growth. Our results reveal that Cu is mobilized to urine during UTI caused by the major uropathogensProteus mirabilisandKlebsiella pneumoniae, in addition to UPEC, in humans. Ceruloplasmin, a Cu-containing ferroxidase, is found at higher levels in UTI urine than in healthy control urine and serves as the molecular source of urinary Cu during UTI. Our results demonstrate that ceruloplasmin decreases the bioavailability of iron in urine by a transferrin-dependent mechanism. Experimental UTI with UPEC in nonhuman primates recapitulates the increased urinary Cu content observed during clinical UTI. Furthermore, Cu-deficient mice are highly colonized by UPEC, indicating that Cu is involved in the limiting of bacterial growth within the urinary tract. Collectively, our results indicate that Cu is a host effector that is involved in protection against pathogen colonization of the urinary tract. Because urinary Cu levels are amenable to modulation, augmentation of the Cu-based host defense against UTI represents a novel approach to limiting bacterial colonization during UTI.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Hyre
authors.affiliation: Department of Pathology/Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Kylie
authors.initials: K
authors.lastname: Kavanagh
authors.affiliation: Department of Pathology/Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Kock
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Donati
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA ssubashc@wakehealth.edu.
authors.forename: Sargurunathan
authors.initials: S
authors.lastname: Subashchandrabose
mesh_terms: D000818:Animals; D058491:Bacterial Load; D001437:Bacteriuria / Q000382:microbiology* / Q000652:urine*; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000652:urine*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D054884:Host-Pathogen Interactions; D006801:Humans; D007477:Ions / Q000652:urine; D051379:Mice; D011323:Primates; D013312:Stress, Physiological; D014551:Urinary Tract / Q000378:metabolism / Q000382:microbiology*
chemical_list: D007477:Ions; D003300:Copper; D002570:Ceruloplasmin
keywords: UPEC; UTI; ceruloplasmin; copper; urinary tract infection; uropathogenic E. coli