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E. Coli Shown Able To Live Within Immune System Cells

 

(An abstract from the scientific publication follows)
Bladder infections have long baffled doctors -- and agonized patients -- with their resiliency. A strong dose of antibiotics can bring relief,but the painful infection often returns in as little as a few days.
In a report published in the October 9, 1997 issue of Nature, researchers at Washington University School of Medicine in St. Louis explain why these infections are so hard to beat: E. coli, the most abundant bacterium in the human body and the cause of most bladder infections, can dodge antibiotics by invading the immune-system cells that line the wall of the bladder.
"Before this study, nobody knew that E. coli could live inside immune-system cells," says David M. Baorto, M.D., Ph.D., fellow in laboratory medicine at the School of Medicine and lead author of the study. "They apparently can take shelter in the very cells that usually destroy them."
About half of American women experience bladder infections at least once during their lifetime, and up to 10 percent suffer three to five infections per year. Antibiotics used to treat these infections may have little effect against bacteria that are hiding in other cells, says co-researcher Soman Abraham, Ph.D., assistant professor of pathology and of molecular microbiology.
Now that physicians are on to E. coli's secret, they may be able to erase more bladder infections by using antibiotics that more thoroughly penetrate cells, he explains.
E. coli usually lives harmlessly in the intestines, but female anatomy makes it easy for the bacterium to get swept into the urinary tract. Once there, the bugs use sticky, hair-like structures called pili to cling to the walls of the urethra and bladder. (Strong adhesives make good sense in an environment constantly flushed with urine. )
To their great surprise, Baorto and colleagues found that the sticky appendages can also work like keys to open up macrophages, immune-system cells that are hearty consumers of bacteria.
Using cultures of mouse macrophages, the researchers discovered that the pili latch onto a particular protein on the macrophage's surface called CD48. Once attached, the bug slides easily into the cell.
After letting E. coli invade the macrophages, the researchers bathed the cells in the antibiotic gentamicin. The bugs on the outside of the cells died quickly, but those inside the macrophages thrived throughout the four-day experiment. "In humans, these bacteria could theoretically escape from the cells and start a new infection," Baorto says.
E. coli is the world's most-studied organism, so why didn't researchers know about this trick? Baorto says the invasion strategy almost never works in places outside of the bladder. Just about anywhere else in the body, an invading E. coli would get quickly covered in antibodies and other small proteins that bind to intruders.
Whencoated in antibodies, E. coli sticks to a different protein on the surface of macrophages -- not CD48 -- with much less pleasant results for the bacteria. Invariably, macrophages consume and quickly kill antibody-covered bugs.
The bladder contains few antibodies, giving E. coli an excellent opportunity to avoid being eaten. Most antibodies produced in the bladder are quickly washed out with the urine, and they don't work well in the acidic environment anyway, Abraham says. In people with compromised immune systems, the bugs may be able to invade macrophages in many parts of the body, he explains.
This research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseasesand a grant from the Barnes-Jewish Hospital Foundation.
Survivalof FimH-expressing enterobacteria in macrophagesrelies on glycolipid traffic
Strains of Escherichia coli persist within the human gutas normal commensals, but are frequent pathogens and cancause recurrent infection.
Here the authors show that, incontrast to E. coli subjected to opsonic interactionsstimulated by the hosts immune response, E. coli thatbind to the macrophage surface exclusively through thebacterial lectin FimH can survive inside the cellfollowing phagocytosis. This viability is largely due tothe attenuation of intracellular free-radical release andof phagosome acidification during FimH-mediatedinternalization, both of which are triggered byantibody-mediated internalization. This differentprocessing of non-opsonized bacteria is supported bymorphological evidence of tight-fitting phagosomescompared with looser, antibody-mediated phagosomes.
The authors propose that non-opsonized FimH-expressing E. coli co-opt internalization of lipid-rich microdomains following binding to the FimH receptor, the glycosylphosphatidylinositol-linked protein CD48, because
  1. the sterol-binding agents filipin, nystatin and methyl -cyclodextrin specifically block FimH-mediated internalization;
  2. CD48 and the protein caveolin both accumulate on macrophage membranes surrounding bacteria; and
  3. antibodies against CD48 inhibit FimH-mediated internalization.
Their findings bring the traditionally extracellular E. coli into the realm of opportunistic intracellular parasitism and suggest how opportunistic infections with FimH-expressing enterobacteria could occur in a setting deprived of opsonizing antibodies.
D M Baorto, Z Gao, R Malaviya, M L Dustin, A van der Merwe, D M Lublin & S N Abraham
(Letter to Nature) Nature 389, 636 (1997)

 

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