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cells, which line the bladder lumen. Following invasion, UPEC grow inside the
cytosol of host cells, giving rise to biofilm-like bacterial aggregates of 10
4
-10
5
bacteria, known as intracellular bacterial communities (IBCs) (
Anderson et al.,
2003
;
Justice et al., 2004
;
Wright et al., 2007
). Type 1 pili are required for the
establishment and maintenance of IBCs, allowing proliferation of UPEC, which
upon maturation can detach and spread to neighboring urothelial cells to con-
tinue the infection cascade. As IBCs have also been observed in human patients
suffering from UTIs (
Rosen et al., 2007
), it is likely that involvement of type 1
pili and IBCs in human UTI is also common.
Another well-studied CU system that is important in urinary tract infec-
tions is P pili, encoded by the
pap
operon. P pilus adhesin PapG was shown to
be important in pyelonephritis in primate models of infection (
Roberts et al.,
1994
). In rat models of infection, P pili were shown to enhance early coloniza-
tion of the kidney tubular epithelium (
Melican et al., 2011
). Most UPEC strains
from human cases of pyelonephritis carry PapGII (
Marschall et al., 2012
;
Otto
et al., 2001
), one of three classes of PapG, which binds to Galα1-4Gal receptor
epitopes in the globoseries of glycolipids found in human renal tissue (
Dodson
et al., 2001
).
In addition to P and type 1 pili's importance in UTIs, various other CU sys-
tems from different species are important in bacterial virulence. For instance,
S pili, encoded by the
sfa
operon, is involved in meningitis (see Chapter 10)
(
Korhonen et al., 1984
;
Morschhauser et al., 1994
), while class 5 ETEC fimbriae
are important for the initiation of diarrheal disease (see Chapter 6) (
Chat-
topadhyay et al., 2012
). Considering the importance of CU pili in infection,
understanding how these pili are assembled and the mechanisms by which they
cause pathogenesis is critical in disease prevention and development of novel
therapeutics.
CU PILI AS ANTIVIRULENCE TARGETS
Antibiotics have led to significant improvements in human health over decades,
improving quality of life and human longevity. However, antibiotic resistance
is escalating (
Boucher et al., 2009
) and multidrug-resistant uropathogens are
spreading globally (
Totsika et al., 2011
). Accompanied by a lack of a significant
effort to develop novel antibiotics and the outstanding risk that antibiotic usage
can negatively impact gut microbiota and result in opportunistic infections, the
search for antivirulence therapeutics is gaining attention. Due to the important
role of CU pili in bacterial virulence, they have been important targets for vac-
cine development studies as well as antivirulence therapeutics. FimH was shown
to be a successful vaccine option in both murine (
Langermann et al., 1997
) and
primate (
Langermann et al., 2000
) models of infection. Keeping in mind the
role of FimH in mediating adhesion with mannosylated uroplakin of uroepithe-
lial cells, alky and phenyl-α-D-mannopyranosides, or mannosides, have been
designed to competitively bind with FimH and interfere with adhesion on host
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