Immunity system complexity: one molecule protects urine (Introduction)

by David Turell , Friday, August 21, 2020, 14:47 (1344 days ago) @ David Turell

The bladder must open to the outside which allows infections in making urine infections common, especially in women. One molecule protects:

https://www.sciencemagazinedigital.org/sciencemagazine/21_august_2020/MobilePagedArticl...

"Human urinary tracts are highly susceptible to bacterial infections. Pathogenic bacteria initiate infections by attaching to sugar chains (glycans) exposed on the surface of the urinary tract epithelium. It has long been suspected that uromodulin (UMOD)—the most abundant protein in human urine—prevents bacteria from binding to urinary tract glycans, thus defending the organism from such infections. However, the mechanism underlying this protection has remained elusive. Now, Weiss et al. reveal, at the molecular level, how UMOD filaments interact with uropathogenic Escherichia coli cells in human urine. These results provide a structural basis for understanding the protective function of UMOD.

***

"Weiss et al. deciphered a comprehensive map of the glycosylation pattern of UMOD, the structure of UMOD filaments, and the nature of bacteria–filament interaction. Infective E. coli cells attach to the urinary tract epithelium through needlelike structures called pili. At their tip, E. coli type I pili consist of the protein FimH (type 1 fimbrin D-mannose specific adhesin). The authors show that the armlike structures extending from UMOD filaments interact with FimH. The interaction between UMOD and FimH is biochemically strong and likely leads to stable binding. Indeed, Weiss et al. show that through this binding, UMOD mediates the stable formation of clumps of bacteria.

"The suggested mechanism of UMOD-based defense is notably simple and robust: The abundant UMOD filaments outcompete receptors on the urinary tract walls in binding to bacterial pili. Each flexible filament has multiple binding sites, and each bacterium can have several pili. Therefore, this multitude of interactions causes bacterial aggregation, effectively preventing individual bacterial cells from attaching to and infecting the urinary tract. In case of the E. coli strain studied by Weiss et al., the interaction between UMOD and bacterial cells occurs through specific binding of FimH to a glycan at asparagine 275 of the UMOD protein.

"However, UMOD contains several other complex glycosylation sites whose functions have not yet been dissected. A compelling possibility is that these serve as binding sites for proteins of other uropathogenic bacteria. In line with this idea, when Weiss et al. imaged urine from patients infected with different bacteria, namely Klebsiella, Pseudomonas, and Streptococcus, the authors found similarly aggregated bacterial cells embedded in UMOD filaments. Given its implication in various aspects of kidney function, UMOD might have other molecular roles that rely on its distinct glycosylation pattern or its adoption of a filamentous structure, besides protection from bacterial infections.

Comment: this highly complex arrangement of active molecules has to be designed. Not by chance! Try to imagine this developing by a hunt-and-peck process of rial and error.