Traveler's diarrhea goes by many names, depending on where in theworld it strikes its unwary or unlucky victim: e.g., in Mexico,Montezuma's revenge; in Egypt, gyppy tummy; in general, the touristtrots.
In an estimated 95 out of 100 cases, the perpetrator of thegastrointestinal distress is Escherichia coli, a bug that was present atthe creation of molecular genetics. Actually, this bacterium inhabitsthe mammalian gut, where it helps to break down food, andsynthesizes the vital blood-coagulating vitamin K.
A gram of human fecal material contains anywhere from 10 to 100million copies of E. coli. The microbe's anal point of departure fromthe body is physically adjacent to the site of urinary excretion, wherethe urethra empties to the outside world.
Thereby hangs one of the commonest female complaints _ urinarytract infection (UTI). "Six to seven million of all women in the U.S.will get at least one UTI during their lifetime," said research urologistXue-Ru Wu of New York University (NYU) School of Medicine.
"The rate of incidence is very high," Wu told BioWorld Today, "and20 percent of UTI patients will suffer recurrences of the infection.Many of them will develop resistance to the antibiotics used to treatit."
Although annoying and often painful, UTI in urethra and bladderusually clears up with treatment, Wu observed. But if it spreadsupstream via the ureters into the kidneys, there causingpyelonephritis, "UTI in the upper urinary tract has a relatively highmorbidity and mortality," he added.
That's why the urology research lab that Wu heads at NYU isexploring just how E. coli gains a foothold in the lining of the urinarytract. He is first author of a paper in today's Proceedings of theNational Academy of Sciences (PNAS) dated Tuesday, Sept. 3, 1996.His co-author is urologist and dermatologist Tung-Tien Sun.
Just as super-smooth, flat, seamlessly joined endothelial cells pavethe network of blood vessels all the way from heart, arteries, andveins to capillaries, so urothelial epithelial cells line the urinary tractfrom the kidneys, where urine arises, down the ureters into thebladder, and out through the urethra.
"We think the adherence of the bacterium to the surface of theepithelium is a very important first step in UTI," Wu observed.
He focused initially on the so-called asymmetrical unit membrane(AUM), which covers 80 percent of the urothelial surface. "ThisAUM," he said, "is very important in initiating the attachmentbetween the bacterium and the urothelium."
Domesticated strains of E. coli, which perform community service inthe human intestine, have smooth outer coats. Their criminal,uropathogenic counterparts are covered with microscopic bristles,called fimbriae or pili. These stubby whiskers, only one or twomicrons long, terminate in adhesins _ antigenic molecules that latchon to the AUM by a mechanism that the NYU urologists report intoday's PNAS.
He and his co-authors radiolabeled cultures of E. coli and incubatedthem with the various protein components of AUM. "We analyzedwhich bacteria bind to which component," he explained. "In thatexperiment we could identify two major glycoproteins, which wenamed uroplakin 1-a and 1-b. They are potential receptors for theadhesins on E. coli's type-1 fimbriae."
That coupling of bacterial adhesin to those urothelial receptors, Wuand his co-authors report, is brokered by mannose, a sugar in the twouroplakin glycoprotein receptors.
"Mannose provides a way," Wu pointed out, "for the bacterialattachment to reach the urinary bladder, and possibly ascend throughthe ureters to the kidneys."
No sugar other than mannose, his team determined, can mediate thatreceptor binding. This suggests a therapeutic strategy to prevent ortreat UTI.
"The potential application of our work," Wu suggested, "may bebeing able to design a drug _ a mannose analogue _ which cansaturate the binding of the bacterial fimbriae. For example," heconcluded, "you could just throw in some mannose analogues. Theywould combine with E. coli's type-1 fimbriae. Then these could nolonger bind to our receptors. It's an inhibitionary approach."
Microbiologists from the University of Lund, Sweden, report in thesame PNAS that "Type 1 fimbrial expression enhances E. colivirulence for the urinary tract."
Studying 88 children ranging in age from two months to six years,they determined that initial attacks of UTI progressed to acutepyelonephritis more virulently when the strain of E. coli infectingthem expressed type-1 fimbriae rather than another, type-1-negative,bacterial serotype.
"That's consistent with our study," Wu said.
Bacterium's Adhesion Game Revealed
A hunger for iron is what drives E. coli to urothelial attachment, saysan article in the current issue of Science, dated Aug. 30, 1996. Itstitle: "Induction of gene expression in Escherichia coli after pilus-mediated adherence."
The paper's first author, Jian Ping Zhang, said: "The novel aspect ofthis work is how attachment is linked to production of a protein thatenables the bacterium to obtain iron from urine, and therefore tosurvive."
Zhang performed this research as a postdoctoral fellow in themolecular biology department at Washington University School ofMedicine, in St. Louis. He now is at Microcide Pharmaceuticals Inc.in Mountain View, Calif.
"The pilus was known to be important for colonization," Zhangexplained. "But we wondered if it doesn't also act as an antenna thatsends a signal back to the bacterium, saying `You have arrived at theright place. Start growing!'"
He and senior author Staffan Normark of Sweden's KarolinskaInstitute in Stockholm, tracked down a gene that kicks in only whenadhesins at the tips of pili make contact with urothelial receptors.They generated a knockout mutant, lacking this gene, which couldnot grow in urine.
What's more, it couldn't make small molecules called siderophores,which scavenge iron.
"So we found that the mutant was unable to survive in low-ironconditions," Zhang explained. "The kidney maintains such anenvironment, so E. coli normally secretes siderophores to competewith the body for iron. Attachment to cells somehow activates thisgene, triggering production of this iron-acquiring system. So P-pilialso function as sensing organelles."
Knocking out this sensing mechanism, he concluded, mighteventually lead to new treatments for kidney and urinary tractinfections." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.