Nature Medicine - 13, 531 - 532 (2007) doi:10.1038/nm0507-531
Flushing bacteria out of the bladder
Danelle S Eto & Matthew A Mulvey
The authors are in the Division of Cell Biology and Immunology, Pathology Department, University of Utah, Salt Lake City, Utah 84112, USA.
A drug that elevates host cAMP levels forces pathogenic bacteria out of bladder epithelial cells. This process may make urinary tract infections more amenable to treatment with antibiotics (pages 625-630).
With over one hundred million infections annually, urinary tract infections (UTIs) remain among the most common infectious diseases worldwide, despite improved hygiene and widespread antibiotic use1.
Even with antibiotic treatment, UTIs can linger and recur in many individuals, such that 25% of women have recurrent symptoms within six months of an initial acute infection2.
The rise of antibiotic-resistant strains of uropathogenic bacteria threatens to worsen the situation. Consequently, there is a need to improve current UTI treatment and prevention protocols.
In a study published in this issue, Bishop et al. provide evidence that forskolin, a compound that raises intracellular levels of cyclic adenosine monophosphate (cAMP), may be useful for combating UTIs3.
More than 80% of community-acquired UTIs are caused by strains of uropathogenic Escherichia coli (UPEC)4. These pathogens typically produce adhesive hair-like fibers called type 1 pili (or fimbriae) that promote attachment to and invasion of bladder epithelial cells.
Once in the host cell, UPEC can withstand antibiotic treatments5, potentially serving as a reservoir for recurrent acute infections6, 7. If so, elimination of intracellular bacterial reservoirs from the urinary tract may provide a means to limit, or even cure, chronic and recurrent UTIs.
The bladder epithelium is composed of a layer of terminally differentiated superficial umbrella cells covering two or more layers of immature intermediate and basal epithelial cells.
UPEC can invade all layers of this stratified epithelium, but the umbrella cells lining the lumenal surface of the bladder are by far the most susceptible to infection6. The apical surfaces of umbrella cells are embedded with plaques of integral membrane proteins known as uroplakins8.
These plaques are thought to contribute to the permeability barrier formed by the bladder epithelium, providing structure and limiting the diffusion of unwanted solutes into the bladder tissue. Nascent uroplakin plaques are assembled into discoidal or fusiform-shaped vesicles that accumulate beneath the apical surface.
As the bladder fills and empties, exocytosis of these vesicles is coordinated with the endocytosis of older uroplakin plaques, increasing and decreasing the lumenal surface area of the bladder as needed.
Trafficking of the fusiform vesicles to the plasma membrane is regulated in part by intracellular cAMP and calcium levels as well as the small GTPase Rab27b8, 9. In these respects, fusiform vesicles behave similarly to secretory lysosomes, which store and secrete cellular components and participate in the repair of damaged plasma membrane10.
At least one pathogen, Trypanosoma cruzi, exploits these organelles to gain access to the cytoplasm of targeted cells. This parasite can invade cells by inducing the exocytosis of host cell secretory lysosomes, a gradual cAMP-regulated process that provides membrane for the formation of T. cruzi-containing vacuoles11.
Knowing all this, Bishop et al. asked whether the uroplakin vesicles might contain UPEC and spit them out into the lumen of the bladder under the control of cAMP3. Could such a process contribute to the uptake and re-emergence of UPEC?
In umbrella cells of infected mice, the authors found that UPEC often colocalize with Rab27b and CD63, a marker of lysosomes and late endosomes. In a human bladder epithelial cancer cell line, E. coli stimulated the extracellular release of the lysosomal enzyme -hexaminidase, while the knockdown of Rab27b expression inhibited type 1 pili-mediated bacterial invasion.
On the basis of these and related observations, the authors suggest that UPEC, like T. cruzi, can induce the exocytosis of secretory lysosomes (or fusiform vesicles), allowing UPEC entry into target host cells. Once the bacteria were internalized, most were rapidly cycled through the host cell and externalized--consistent with previous studies6, 7. Bishop et al. went on to show that, like uroplakin fusiform vesicles and secretory lysosomes, the re-emergence of UPEC is regulated by calcium and cAMP levels3.
In addition, the authors show that treatment with forskolin, which increases cAMP levels, reduced the levels of intracellular bacteria in the bladders of infected mice, presumably by stimulating the exocytosis of UPEC-containing vesicles.
With this key observation, the authors discovered a way to possibly target intracellular reservoirs of UPEC: by forcing their release into the extracellular space where they can be more easily killed by traditional antibiotic treatments.
Forskolin is the main active ingredient of the Ayurvedic herb Coleus forskohlii, a member of the mint family found in subtropical regions in Asia. Owing to its capacity to raise intracellular levels of cAMP, forskolin is used to treat several ailments, including allergies, respiratory problems such as asthma, glaucoma and cardiovascular diseases.
Although the use of forskolin as a potential therapeutic for UTIs is intriguing, several questions remain. Among these is whether or not forskolin treatment alone or in combination with antibiotics can reduce bacterial titers within infected bladder tissue more effectively than antibiotics alone.
In addition, UPEC can follow at least three paths within host cells, not all of which may be affected by forskolin treatment (Fig. 1). In the first pathway, highlighted by Bishop et al., many of the internalized UPEC are released back into the extracellular space via a cAMP-mediated, forskolin-stimulated process3.
Alternately, UPEC can become sequestered within late endosome/lysosome-like compartments where the pathogens can persist in a nonreplicating state, forming quiescent intracellular reservoirs from which UPEC may eventually re-emerge to cause recurrent acute infections (Fig. 1 and ref. 6).
Finally, microbes that manage to enter the cytoplasm of umbrella cells can rapidly multiply, forming large intracellular inclusions (Fig. 1 and refs. 7,12). The effects of forskolin treatment on such reservoirs and inclusions, and the persistence and recurrence of UTIs, remain to be tested.
[ 12. May 2007, 08:53 AM: Message edited by: lou ]
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bettyg
Unregistered
posted
hello to my dear friend lou,
i was interested in this since i've had recent urinary bacteria infections and treated.
however, i had to stop reading when i hit the long, solid blocks of text.
any chance you could edit by using pencil icon on those LONG paragraphs only breaking them up into 2 or 3 paragraphs if they are especially long so we can comprehend/read them?
thanks for your consideration lou! take care.
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I got rid of one recently with colloidal silver, and I didn't get a yeast infection from antibiotics.
At least the silver kills germs and yeasts, I have read. I understand it is an equal-opportunity bug killer.
Susan
P.S. I get more out of it taking it empty, and then I hold it under my tongue as long as possible.
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