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Architecture and function of human uromodulin filaments in urinary tract infections

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Science  21 Aug 2020:
Vol. 369, Issue 6506, pp. 1005-1010
DOI: 10.1126/science.aaz9866

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How uromodulin helps flush out bacteria

Urinary tract infections (UTIs) are one of the most frequent bacterial infections in humans. The glycoprotein uromodulin is the most abundant urinary protein and can provide some protection from UTIs, but the precise mechanism has been unclear. Weiss et al. found that uromodulin forms stacked, fishbone-like filaments that act as a multivalent decoy for bacterial pathogens with adhesive pili that attach to the uromodulin glycans (see the Perspective by Kukulski). The resulting uromodulin-pathogen aggregates prevent bacterial adhesion to glycoproteins of the urinary epithelium and promote pathogen clearance as urine is excreted. This innate protection against UTIs is likely to be particularly important in infants and children.

Science, this issue p. 1005; see also p. 917

Abstract

Uromodulin is the most abundant protein in human urine, and it forms filaments that antagonize the adhesion of uropathogens; however, the filament structure and mechanism of protection remain poorly understood. We used cryo–electron tomography to show that the uromodulin filament consists of a zigzag-shaped backbone with laterally protruding arms. N-glycosylation mapping and biophysical assays revealed that uromodulin acts as a multivalent ligand for the bacterial type 1 pilus adhesin, presenting specific epitopes on the regularly spaced arms. Imaging of uromodulin-uropathogen interactions in vitro and in patient urine showed that uromodulin filaments associate with uropathogens and mediate bacterial aggregation, which likely prevents adhesion and allows clearance by micturition. These results provide a framework for understanding uromodulin in urinary tract infections and in its more enigmatic roles in physiology and disease.

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