Urinary tract infections (UTIs) are one of the most common bacterial infections and are predominantly caused by uropathogenic Escherichia coli (UPEC). While UTIs are typically considered extracellular infections, it has been recently demonstrated that UPEC bind to, invade, and replicate within the murine bladder urothelium to form intracellular bacterial communities (IBCs). These IBCs dissociate and bacteria flux out of bladder facet cells, some with filamentous morphology, and ultimately establish quiescent intracellular reservoirs that can seed recurrent infection. This IBC pathogenic cycle has not yet been investigated in humans. In this study we sought to determine whether evidence of an IBC pathway could be found in urine specimens from women with acute UTI.
Methods and Findings
We collected midstream, clean-catch urine specimens from 80 young healthy women with acute uncomplicated cystitis and 20 asymptomatic women with a history of UTI. Investigators were blinded to culture results and clinical history. Samples were analyzed by light microscopy, immunofluorescence, and electron microscopy for evidence of exfoliated IBCs and filamentous bacteria. Evidence of IBCs was found in 14 of 80 (18%) urines from women with UTI. Filamentous bacteria were found in 33 of 80 (41%) urines from women with UTI. None of the 20 urines from the asymptomatic comparative group showed evidence of IBCs or filaments. Filamentous bacteria were present in all 14 of the urines with IBCs compared to 19 (29%) of 66 samples with no evidence of IBCs (p < 0.001). Of 65 urines from patients with E. coli infections, 14 (22%) had evidence of IBCs and 29 (45%) had filamentous bacteria, while none of the gram-positive infections had IBCs or filamentous bacteria.
The presence of exfoliated IBCs and filamentous bacteria in the urines of women with acute cystitis suggests that the IBC pathogenic pathway characterized in the murine model may occur in humans. The findings support the occurrence of an intracellular bacterial niche in some women with cystitis that may have important implications for UTI recurrence and treatment.
Analyzing urine specimens from women with bladder infections, Scott Hultgren and colleagues find evidence for intracellular bacterial communities, which have been associated with recurrent urinary tract infections in mice.
Every year, nearly 10 million people in the United States—mainly women—consult their doctors because of a urinary tract infection (UTI). UTIs occur when bacteria living in the gut—usually Escherichia coli—get transferred to the opening of the urethra (the tube through which urine leaves the body), as may occur during sexual intercourse. From here, the bacteria can move into the bladder (the muscular sac that stores urine until it is excreted) where they can multiply and cause cystitis (inflammation of the bladder). If cystitis is untreated, the bacteria can move further up the urinary tract and infect the kidneys (which make urine). Symptoms of UTIs include pain when urinating, frequent and intense urges to urinate, and cloudy urine. UTIs are diagnosed by looking for bacteria and white blood cells (that fight infection) in the urine; the usual treatment is a short course of antibiotics.
Why Was This Study Done?
Half the women who get a UTI will have another attack within a year, often caused by the same bacterial strain. It is generally thought that these strains persist in the gut and reinfect the urinary tract, but recent animal studies suggest an additional explanation. In mice, E. coli strains that cause UTIs can invade the cells lining the bladder. Here, they replicate and form so-called intracellular bacterial communities (IBCs). Many of the infected cells fall off the bladder's surface into the urine, but IBCs also release bacteria, many of which have a long, slender filamentous appearance (E. coli usually have a simple rod-like shape). Immune system cells normally kill bacteria in the urine but cannot deal with filamentous bacteria. In mice, these bacteria can then reinfect the lining of the bladder and establish long-lasting intracellular reservoirs of bacteria that are protected from antibiotics and probably from the host immune system. If this IBC cycle occurs in people, it might explain why some UTIs recur and might suggest ways to manage these recurrences. In this study, therefore, the researchers have investigated whether there is an IBC cycle in women.
What Did the Researchers Do and Find?
The researchers collected urine from 80 young women with cystitis and from 20 women with no symptoms who had had cystitis previously. They identified the type of bacteria in each sample and looked for IBCs and filamentous bacteria using light microscopy, electron microscopy, and a technique called immunofluorescence. None of the women without cystitis had IBCs or filamentous bacteria in their urine, but IBCs were found in nearly 1 in 5, and filamentous bacteria were in nearly half, of urine samples from the women with cystitis. All the urine samples that contained IBCs also contained filamentous bacteria. All of the women with IBCs and most of them with filamentous bacteria had E coli infections. Finally, the women with IBCs and filamentous bacteria in their urine had higher bacterial counts in their urine and had symptoms of cystitis for slightly longer than those without.
What Do These Findings Mean?
These findings suggest that the IBC cycle identified in mice occurs in at least some women with UTIs and may be associated with infections caused by E. coli. Because only one urine sample was collected from each woman, the cycle may be more common than these findings suggest. That is, in some cases the sample may have been taken at a time when there were no IBCs or filamentous bacteria in the urine. Also, because samples were taken at only one point in time, this study does not show whether intracellular bacteria persist and contribute to recurrent UTIs in women, as they appear to do in mice. To provide more information about the IBC cycle in people and its clinical relevance, additional studies are needed to examine whether there are any associations between the presence of IBCs and filamentous bacteria and treatment responses and recurrence, and to examine what is actually happening in the bladder during UTI. Until such studies are done, the clinical implications of the current findings remain uncertain. However, one possibility is that the presence of IBCs and filamentous bacteria in urine might identify people who would benefit from longer treatment with antibiotics or treatment with antibiotics that kill bacteria inside human cells.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040329.
The MedlinePlus encyclopedia contains pages on urinary tract infection, on cystitis, and on recurrent cystitis (in English and Spanish)
Information is available from the UK National Health Service Direct health encyclopedia on urinary tract infections and on cystitis
The US National Kidney and Urologic Diseases Information Clearinghouse provides information on urinary tract infections (in English and Spanish)
Information is available from the American Urological Association on urinary tract infections in adults