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In-Depth Information
Epidemiology and global impact
Urinary tract infections (UTIs) are the second most common infection of humans,
causing 8.1 million physician visits in the United States in 2007 (
Schappert and
Rechtsteiner, 2008
), and an estimated 10 million cases in western Europe. UTIs
are usually caused by bacteria from the intestinal tract contaminating the peri-
urethral opening, followed by ascension of the urinary tract. Women are more
susceptible to UTI due to the relative proximity of the periurethral space to the
anus and to the fact that the urethra is much shorter than that of men, thus allow-
ing easier access to the bladder by fecal bacteria. It is estimated that over 50%
of all women will have a UTI in their lifetime, 25% will then experience a sec-
ond UTI, and 3% will have a third UTI within 6 months of the initial infection
(
Foxman, 2003
).
E. coli
is the primary cause of UTIs, responsible for an esti-
mated 80% of all uncomplicated UTIs (
Stamm and Hooton, 1993
;
Ronald, 2002
)
and 18-35% of long-term indwelling catheter-associated UTIs (
Nicolle, 2005
).
MOLECULAR PATHOGENESIS
Entry and ascension of the urinary tract
UTIs caused by
E. coli
are ascending infections in which bacterial contami-
nation of the periurethral space allows UPEC access to the otherwise sterile
urinary tract. Ascension of the urinary tract by UPEC is mediated by the action
of flagella, which propel bacteria up the urethra to the bladder, where the bac-
teria utilize a multitude of fimbriae and non-fimbrial adhesins to colonize, iron
acquisition systems to facilitate growth, and toxins to avoid the innate immune
response (
Table 9.1
and
Figure 9.1
). A subpopulation of
E. coli
can detach from
the bladder and move up the ureters to the kidneys (mediated by flagella) (
Lane
et al., 2007a
;
Walters et al., 2012
). Flagellar motility is essential for uropatho-
genesis, as non-motile mutants of UPEC that cannot express FliC, the main
component of the flagellum, are attenuated in the mouse model of ascending
UTI (
Wright et al., 2005
;
Lane et al., 2007a
).
E. coli
reciprocally regulates fim-
brial and flagellar biosynthesis so that when fimbriae are expressed, flagella
are down-regulated causing a shift between motile and sessile lifestyles (
Lane
et al., 2007b
). Several transcription factors, including H-NS (
Korea et al., 2010
),
Lrp (
Simms and Mobley, 2008a
), cAMP-CRP (
Yokota and Gots, 1970
;
Muller
et al., 2009
), and LeuX (
Ritter et al., 1995
), as well as non-specific regulators,
such as DNA topology (
Dorman and Corcoran, 2009
), can affect the switch
between motility and sessility. Most of these transcription factors regulate the
expression of the recombinases FimB and FimE, which affect the orientation
of the promoter of the type 1 fimbrial operon as described below (
Ritter et al.,
1995
;
Simms and Mobley, 2008b
;
Dorman and Corcoran, 2009
;
Muller et al.,
2009
). Simultaneously, the same regulators affect the transcription of
flhDC,
which encode the master regulator of flagellar biosynthesis, in an opposite man-
ner, so that when flagella are expressed, fimbrial biosynthesis is repressed.
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