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Invasion and intracellular bacterial communities
Invasion of epithelial cells by UPEC is a relatively rare event (
Mysorekar and
Hultgren, 2006
). However, in the murine urinary tract, invasion occurs by a zip-
per mechanism in which type 1 fimbriae, or DraD/AfaD bind to receptors on the
host cell that mediate actin cytoskeletal rearrangements (
Zalewska et al., 2001
;
Wang et al., 2008
). Actin filament rearrangement induces a phagocytic cup
that envelops the bacterium, thus allowing entry into the host cell (
Wang et al.,
2008
). In DraD/AfaD-mediated internalization,
E. coli
binds the host cell utiliz-
ing the Dr fimbrial adhesin, DraE/AfaE (
Garcia et al., 2000
). Adherent bacteria
enter the epithelial cell through clathrin-coated vesicles, after a threshold level
of the invasin, AfaD/DraD is achieved (
Zalewska et al., 2001
). Cytotoxic nec-
rotizing factor-1 (CNF-1) toxin, also mediates invasion into host cells by stimu-
lating rearrangement of the actin cytoskeleton (
Falzano et al., 1993
). Once in
the cytosol of the host cell, CNF-1 deamidates glutamine 61 of Rac-1 and glu-
tamine 63 of RhoA activating these Rho GTPases. The Toll-interacting protein
(Tollip) interacts with the activated Rac-1, and binds Tom1, which recruits clath-
rin to the plasma membrane, causing internalization of the bacterium through
the endocytic pathway (
Visvikis et al., 2011
). The active Rho GTPases are then
ubiquitylated and degraded by the proteasome (
Doye et al., 2002
).
Type 1 fimbriae mediate invasion of cultured human and murine mannosyl-
ated superficial umbrella cells, leading to formation of intercellular bacterial
communities (IBCs) (
Martinez et al., 2000
;
Justice et al., 2004
). IBCs develop
in the cytosol from a single bacterium that replicates to form a biofilm-like
community encased in a polysaccharide-rich matrix (
Anderson et al., 2003
).
While the mechanistic basis for IBC formation is not fully understood, three
factors are necessary for complete IBC maturation. First, SurA, a periplasmic
prolylisomerase/chaperone that facilitates biogenesis and assembly of outer
membrane proteins and fimbriae, is essential for both invasion and maturation
of IBCs, demonstrating that fimbriae and/or other outer membrane proteins are
involved in bacterial uptake and IBC development (
Justice et al., 2006b
). Second,
OmpA, an outer membrane protein, promotes IBC maturation, as disruption
of
ompA
does not affect adherence or invasion of bladder epithelial cells, but
leads to significantly lower numbers of IBCs. This defect was complemented,
demonstrating the decrease in mature IBCs was due to the loss of OmpA
(
Nicholson et al., 2009
). Finally, the K capsule polysaccharide itself is neces-
sary for IBC formation (
Goller and Seed, 2010
). After IBCs are fully matured,
UPEC undergo a morphological change into a filamentous form. These fila-
mentous bacteria then escape into the lumen of the bladder in a process called
fluxing, which allows the infection to spread to other bladder cells or ascend the
urinary tract (
Mulvey et al., 2001
). The phenomena of fluxing and IBC forma-
tion led to the hypothesis that recurrent UTIs are caused by UPEC that avoid
killing by antibiotics by persisting in IBCs, followed by reemergence into the
bladder lumen by fluxing. However, this has yet to be substantiated in humans.
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