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Intracellular Lifestyles and

Immune Evasion Strategies of
Uropathogenic Escherichia coli
David A. Hunstad1 and Sheryl S. Justice2
1
Departments of Pediatrics and Molecular Microbiology, Washington University School of
Medicine, St. Louis, Missouri 63110; email: dhunstad@wustl.edu
2
Center for Microbial Pathogenesis, Research Institute at Nationwide Childrens Hospital,
Columbus, Ohio 43205; email: sheryl.justice@nationwidechildrens.org
Annu. Rev. Microbiol. 2010. 64:20321
Key Words
First published online as a Review in Advance on

June 2, 2010
urinary tract infection, epithelium, biolm, community, neutrophil
The Annual Review of Microbiology is online at

micro.annualreviews.org
Abstract
This articles doi:

10.1146/annurev.micro.112408.134258
c 2010 by Annual Reviews.
Copyright
All rights reserved
0066-4227/10/1013-0203$20.00
Paradigms in the pathogenesis of urinary tract infections have shifted

dramatically as a result of recent scientic revelations. Beyond extracellular colonization of the bladder luminal surface, as traditional clinical
thinking would hold, uropathogenic bacteria direct a complex, intracellular cascade that shelters bacteria from host defenses and leads to
persistent bacterial residence within the epithelium. After epithelial invasion, many organisms are promptly expelled by bladder epithelial
cells; a minority establish a niche in the cytoplasm that results in the development of biolm-like intracellular bacterial communities and serves
as the primary location for bacterial expansion. Exfoliation of the supercial epithelial layer acts to reduce the bacterial load but facilitates
chronic residence of small nests of bacteria that later reemerge to cause
some episodes of recurrent cystitis, a familiar clinical scenario in otherwise healthy women. Advances in both in vitro and animal models of
cystitis promise to provide insights into the bacterial and host transcriptional and biochemical pathways that dene these pathogenic stages.
203
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Contents

URINARY TRACT INFECTIONS . .

ADHESION AND
EPITHELIAL INVASION . . . . . . . .
INTRACELLULAR GROWTH
DURING ACUTE CYSTITIS . . . .
INNATE AND ADAPTIVE
RESPONSES TO URINARY
TRACT INFECTIONS . . . . . . . . . . .
IMMUNE EVASION STRATEGIES
OF UPEC . . . . . . . . . . . . . . . . . . . . . . . . .
ESTABLISHMENT OF THE
QUIESCENT
INTRACELLULAR
RESERVOIR. . . . . . . . . . . . . . . . . . . . . .
SUMMARY AND
FUTURE PROSPECTS . . . . . . . . . .
204
205
206
210
212
214
215
URINARY TRACT INFECTIONS

The human urinary tract is one of the most
common sites for bacterial infection. Uncomplicated urinary tract infections (UTIs) account
for over 14 million medical visits and almost
$4 billion in medical expenditures each year
in the United States alone (59). In addition
to structural and urodynamic abnormalities
(either biological or healthcare associated),
pregnancy (5), diabetes (80), bladder catheterization (71), prostate enlargement (59), HIV infection (32), and sexual activity (27, 88) have
been described as predisposing factors for the
development of UTIs. However, most outpatients with UTI are otherwise healthy women
with no identiable risk factors. About 50% of
women will experience a UTI at some point
in life, while 25% will experience a second
UTI and 3% will experience a third UTI in
the six months following treatment of initial
UTI (33). There exists a clear need to better understand the processes underlying recurrence in these women. Restriction fragment
length polymorphism analysis of recurrent infections in 58 women demonstrated that 68%
of recurrences arose from the same bacterial
UTI: urinary tract

infection
UPEC:
uropathogenic
Escherichia coli
204
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strain as that causing the initial infection (83).

Same-strain recurrent infections have been observed up to 3 years after an initial UTI (14,
33). The index strain was identied in the vaginal and fecal cultures of some patients within
these studies, suggesting that recurrent UTIs
are caused by reintroduction of a virulent strain
into the urethra. However, daily topical antibiotic treatment in the perineum did not prevent recurrent infections (15), suggesting that
pathogen migration from the anus to the urinary tract is not required for recurrence of UTI.
Uropathogenic Escherichia coli (UPEC)
cause up to 90% of all diagnosed UTIs (33)
and are the leading cause of both communityacquired and healthcare-associated UTIs.
Although as a group urinary tract infections
are caused primarily by UPEC, it is important
to emphasize that cystitis and pyelonephritis
are not the same disease. Just as multiple E.
coli pathotypes (e.g., EHEC, ETEC, EHEC)
cause distinct gastrointestinal diseases (20),
UPEC use distinct virulence determinants to
cause disease in the bladder (cystitis) and in the
kidney (pyelonephritis). Clinically, cystitis and
pyelonephritis share the features of bacteria
in the urine (bacteriuria), leukocytes in the
urine (pyuria), urgency, frequency, and painful
urination (dysuria). However, pyelonephritis
is distinguished clinically from cystitis by
the presence of ank pain, fever, nausea, and
vomiting. In addition, ndings on radiologic
examination of the kidneys (e.g., renal enlargement and/or echogenicity on ultrasound
examination) may help to dene upper tract
involvement in UTI patients. It is possible that
a proportion of patients diagnosed with cystitis
also have bacterial colonization of the kidney(s)
that does not elicit the overt symptoms typically associated with pyelonephritis. Finally,
patients that present with pyelonephritis may
or may not also have cystitis, as infection
of the kidney may arise from ascending or
hematogenous routes. Because there is no
routine clinical test that denes which urinary
tissues are involved in an infection, classication of tissue tropism for each clinical isolate is
limited to patient symptomatology. Therefore,
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it can be difcult to ascertain specic bacterial

virulence traits that associate only with cystitis
or pyelonephritis. Because of space limitation
and given our personal experience, we conne
our subsequent discussion of pathogenesis
primarily to infections of the bladder.

ADHESION AND
EPITHELIAL INVASION
Bacteria that are unable to adhere to host tissues are unable to cause disease. This axiom is
true of many bacterial pathogens and has been
clearly demonstrated in the development of cystitis and pyelonephritis caused by UPEC, which
can produce a variety of surface-associated proteins that serve as adhesins (105). Within the
urinary tract, UPEC produce at least two heteropolymeric, proteinaceous extracellular organelles, termed pili, that mediate adhesion to
specic receptors on the uroepithelium. UPEC
genomes typically contain multiple discrete loci
encoding highly resilient pili that are assembled via the canonical chaperone/usher secretion pathway (105). The type 1 pilus adheres to
mannosylated uroplakin proteins on the luminal surface of the bladder (109), while P pili bind
to globoseries glycolipids on the kidney epithelial surface (24). Because of high similarity to
humans in the expression of these receptors and
in other morphological features, the mouse has
Table 1
emerged as a key model for the study of epithelial binding and many subsequent pathogenic
events in cystitis.
For years, UTIs have typically been considered an extracellular, self-limiting acute
infection. However, a number of studies using
in vitro and in vivo models for UTIs have
demonstrated that UPEC are invasive to
supercial bladder epithelial cells (4, 10, 13,
25, 26, 2830, 6264, 67, 87, 94, 100, 107) and
kidney epithelial cells (17, 74). Invasion into
bladder epithelial cells has also been observed
with other common uropathogens, including
Staphylococcus saprophyticus (99), Klebsiella pneumoniae (82), and Salmonella enterica (13). Host
and bacterial factors that play a role in UPEC
invasion into bladder epithelial cells are listed in
Tables 1 and 2. Unlike some other gramnegative pathogens, UPEC do not appear to actively direct their invasion process; that is, there
are no identied bacterial effectors that stimulate UPEC invasion. Moreover, with a given
population of bound bacteria after experimental
inoculation of murine bladders, at most 100fold-fewer invasion events are detected, suggesting that bacterial binding is not sufcient
to ensure internalization (50, 107). Recent data
suggest that UPEC are taken up in Rab27bpositive fusiform vesicles, which are normally
shuttled into and out of the apical membrane
to regulate bladder surface area during the
Host factors implicated in UPEC internalizationa

Cystitis
Pyelonephritis
Attach
Invade
Expel
Attach
Invade
Actin
(30)
(30)
cAMP
(13)
(13, 95)
Caveolae
(26)
(95)
(17)
Clathrin
(17)
Integrin
(29)
(29)
Lipid rafts
(26)
(17)
MyRIP
(95)
Rab27b
(13)
(95)
TLR4
(95)
(95)
(17)
Uroplakin Ia
(109)
Pili: heteropolymeric,
proteinaceous bers
produced on the
surface of UPEC that
promote adhesion to
host tissues
References are given in parentheses.
www.annualreviews.org Pathogenic Lifestyles of UPEC
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Table 2
Selected UPEC factors that contribute to intracellular pathogenesis and immune evasion

Lifestyle
Function
Protein(s)
Adhesin
FimH
92, 107
IBC formation
Adhesin
General metabolism
Motility
Outer membrane
sRNA
tRNA
Two-component system
FimH
DppA, OppA, TpiA, SdhB, PckA
MotAB, CheW
SurA, OmpA
Hfq
LeuX
QseC
92, 107
1
58
50, 70
56
36
54
Filamentation
Cell division
SulA
QIR formation
Cell division
Motility
Outer membrane
SulA
FliC
SurA, OmpA
49
57, 58, 106
50, 70
Immune evasion
Capsule
Cell division
sRNA
Stress responses
Leukotoxin
Signal inhibitor
LPS presentation
KpsC
SulA
Hfq
RpoS, RpoE, RecA, LexA
Cnf1
TcpC
AmpG, WaaL, Rfa, Rfb, SurA
8
49
56
56, 58a
22, 23, 55
19
12, 42, 101
accumulation of urine. As a further result of

this vesicle trafc, a proportion of internalized bacteria is returned to the extracellular
environment by exocytosis (13). Treatment of
epithelial cells with agents such as forskolin,
which induces exocytosis of fusiform vesicles
by elevating intracellular cyclic AMP, results
in diminished bacterial loads (but not complete
eradication) in the murine bladder (13, 30),
indicating that promotion of exocytosis might
aid in the treatment of UTIs.
A minority of internalized UPEC appear
to gain unrestricted access to the cytoplasm
during cystitis and begin an exponential phase
of growth, which is discussed further in the
following section. Growth within the cytoplasm of cultured bladder epithelial cells occurs
when detergents are added postinvasion (30),
demonstrating that escape from the membranebound compartment is sufcient to promote
intracellular growth. It is unclear whether
the cytoplasmic subpopulation arises from a
downstream event of the invasion mechanisms
indicated (Table 1) or through an alternative, yet undescribed, pathway of invasion.
206
Reference(s)
Attachment
Hunstad
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49
Regardless of the mechanism, this cytoplasmically located subpopulation of UPEC is

the ultimate source for ongoing colonization,
expansion of the intracellular burden, and
eventual bacterial persistence within the
uroepithelium. Thus, successful UPEC must
navigate several potential bottlenecks (invasion,
avoidance of expulsion, and escape into the cytoplasm), each of which reduces the diversity of
the UPEC population that goes on to cause disease within an individual. The presence of these
bottlenecks, combined with the observation of
same-strain recurrences in women, further underscores the presence of a reservoir of bacteria
within the urinary tract (discussed below).
INTRACELLULAR GROWTH
DURING ACUTE CYSTITIS
Visualization of explanted bladders from
C3H/HeN mice by time-lapse uorescence microscopy revealed that UPEC proceed through
a complex developmental and differentiation
pathway during experimental cystitis, multiplying in number and evading host immune
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effectors by establishing a niche within supercial epithelial cells of the bladder (46). The
developmental pathway includes two independent branches that exhibit different patterns
of morphological differentiation. The developmental pathway during UPEC cystitis begins
with all bacteria in the bacillary shape (ca. 1
3 m), doubling every 30 min within loosely
associated intracellular bacterial communities
(IBCs) (Figure 1 and Figure 2a). Most bacteria are routed along the rst differentiation
branch, synchronously dividing at a shorter cell
length to yield daughter cells that are coccoid in shape (ca. 1 1 m). This coccoid
shape allows approximately 105 106 organisms
to be packed within each infected supercial
facet cell (pod) (4), approximately two orders
of magnitude more efcient than the packing
Superficial
Acute cycle
termination
Transitional
Attach
Egress
Invade
Acute
infection
cycle
Exfoliate
PMN
Late
Early
Invade
Middle
Epithelial cell
Bacterium
Host nucleic acids
QIR
PMN
Filamentous UPEC
Figure 1
Schematic representation of the intracellular lifestyles of uropathogenic Escherichia coli (UPEC). Each stage of the developmental cycle
and the accompanying morphological changes are depicted in a series of supercial bladder epithelial cells. Following invasion, UPEC
is either expelled or gains access to the cytoplasm (indicated by small arrows). The acute infection consists of six stages that occur in
multiple rounds as indicated by the circular arrows. The acute infection terminates with the exfoliation of the entire supercial bladder
cells. The presence of bacteria within the urine at the time of exfoliation leads to the establishment of a quiescent intracellular reservoir
(QIR) that can serve as the source of recurrent urinary tract infections. The bacteria remain viable for months within the bladder tissue
despite the absence of bacteria in the urine. PMN: polymorphonuclear leukocyte. Reproduced with permission from Reference 46.
Copyright (2004) National Academy of Sciences U.S.A.
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6h
UT189
(green
fluorescent
protein)
Surface
(wheat germ
agglutinin)

Nucleic acid
(Hoescht)
10 m
16 h
16 h
14 days
Figure 2
Fluorescence micrographs of uropathogenic Escherichia coli (UPEC) lifestyles during cystitis. Female mice were transurethrally infected
with UTI89 carrying a plasmid-encoded green uorescent protein (green). Bladders were harvested, bisected, xed in 3%
paraformaldehyde, and surface visualized with wheat germ agglutinin (red), and nucleic acids were visualized with Hoechst (blue) at
(a) 6 h, (b, c) 16 h, and (d) 14 days postinfection. Scale bars all show 10 m.
Intracellular
bacterial community
(IBC): a biolm-like
collection of
intracellular bacteria
that participate in the
UPEC intracellular
differentiation and
developmental cycle
during the acute phase
of cystitis
Pod: a supercial
bladder epithelial cell
that hosts an IBC,
often protruding into
the lumen of the
bladder as the IBC
expands
208
of unorganized bacillary forms. Being located

at the center of such an intracellular community has obvious potential benetit is protected from epithelium-derived and exogenous
antimicrobial agents (18, 69). Furthermore, the
decreased size of each bacterium might itself
afford relative protection from phagocytosis, as
observed in some predator-prey interactions in
marine environments (73). Subsequently, the
architecture of the UPEC community evolves
toward an overall globular shape (Figure 1 and
Figure 2b). The coccoid shaped bacteria at
the periphery of the IBC regain a bacillary
shape, become highly motile, and exit the infected epithelial cell through disruptions in the
cell membrane (Figure 1) to attach to nave
Hunstad
Justice
epithelial cells or to leave the host through micturition. At late stages of IBC maturation, much
of a facet cells cytoplasm can be occupied, and
many pods are undergoing apoptosis and cell
death (52, 66, 101, 102).
The evolution of UPEC community architecture is reminiscent of changes observed during the maturation of biolms formed by various bacteria (e.g., Pseudomonas aeruginosa or
enterococci). Therefore, the same protection
against stresses and antimicrobials conferred
to bacteria growing within biolms (3) might
also be conferred to bacteria growing within an
IBC. The motility and dispersion of the bacteria from the community are also classic characteristics of biolms, and there is overlap in

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bacterial factors that participate in the formation of IBCs and biolms on abiotic surfaces
(Table 2). A recent denition of a microbial
biolm is a community of microbes associated
with a surface and typically encased in an extracellular matrix (65). Although IBC-forming
UPEC do not have handy a traditional surface (e.g., rock, tooth, or indwelling catheter),
numerous membrane surfaces within the epithelial cell (e.g., endoplasmic reticulum, Golgi
body, nuclear membrane) could serve as a substratum for biolm-like development of the
IBC. In fact, the initial point of IBC formation is
often tightly juxtaposed with the nucleus of the
supercial bladder epithelial cell (Figure 2a,
inset), and the cells nuclei and other organelles are often seen embedded within the
IBC proper. Because bacterial communities
that assemble on the exterior of epithelial layers are generally accepted as biolms, consideration of bacterial communities that form on intracellular membrane surfaces as biolms seems
equally valid.
During the early stage of the IBC pathway, a minority of the UPEC population proceeds through a second differentiation branch
that ultimately results in the formation of lamentous bacteria (up to 70 m in length)
(Figure 2c). These bacteria become lamentous during the intracellular stage and egress
along with the bacillary shaped bacteria to
reattach to the luminal surface of the bladder epithelium. Enrichment of the lamentous
forms occurs as a result of preferential consumption of bacillary shaped bacteria by host
phagocytes (Figure 2c) (46, 49; D. Horvath &
S. Justice, unpublished data). The lamentous
UPEC, now extracellular, later reinitiate septation to produce daughter cells of normal bacillary length that remain attached to the bladder
surface (46).
Attachment to nave supercial facet epithelial cells then initiates subsequent rounds
of IBC formation. During experimental UTI
in the murine model, the rst round of IBC
formation proceeds with remarkable synchronization. However, because of variable times of
egress from each pod, subsequent rounds occur
with an asynchronous distribution. With typical

inocula of UPEC during experimental murine
cystitis (107 colony-forming units), as many
as several hundred pods can be produced. Because human UTI arises from a presumably
lower inoculum, cystitis might even be initiated
by infection of just one supercial epithelial
cell with a single bacterium that gains access to
the cytoplasm. With each round of IBC formation there is signicant loss of bacteria into the
urine through egress and epithelial exfoliation,
but UPEC are amplied intracellularly and the
infection is extended to form new pods. In
addition, IBC formation might serve to select
organisms with characteristics optimized for intracellular life, subversion of immune effectors,
and intraepithelial persistence.
The presence of numerous phenotypic
stages in the developmental cycle of UPEC
suggests that multiple gene products are required for optimal growth, community development, and disease causation. Many labs have
used targeted gene inactivation to identify bacterial traits essential for the pathogenesis of
UPEC cystitis (Table 2). In most cases, the defects associated with attenuated virulence occur
postinvasion, except for the case of type 1 pili.
One might expect that the pilus would be required only for adhesion and internalization.
But considering that type 1 pili are essential
for biolm formation in vitro (77), and because
IBC development parallels biolm formation,
one might also surmise that type 1 pili would
have additional roles in the intracellular niche.
Although intracellular growth can be observed
when type 1 piliation is abrogated following epithelial internalization, bacteria under this condition appear dispersed, rather than forming
an organized community (107). The dispersed
phenotype of the type 1 pilusdecient UPEC
is associated with a 2-log reduction in bacterial burden (107), further indicating that biolm
formation and maturation in the middle IBC
stage increase the potential for bacterial growth
within the epithelial cell.
Another interesting requirement for intracellular growth relates to outer membrane
biogenesis. Inactivation of a periplasmic
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cis-trans peptidyl prolyl isomerase, SurA,

results in deciencies in the assembly of
outer membrane proteins (OMPs) (48, 103)
but has minimal effects on bacterial growth
in rich laboratory conditions. In contrast,
UPEC strains decient in the production of
SurA are defective in epithelial invasion and
intracellular growth. Type 1 pilus assembly
requires SurA (48), but the UPEC SurA mutant
remains defective intracellularly even when
piliation is corrected (50), suggesting that other
SurA-dependent OMPs are required for intracellular pathogenesis. The rst such OMP,
namely outer membrane protein A (OmpA),
was recently shown to be required for IBC
formation and persistent infection (70). Thus,
the cytoplasm of uroepithelial cells represents
a unique milieu that requires the expression of
specic proteins for UPEC growth, perhaps
for nutrient uptake, interbacterial interaction,
and/or protection from host products.
The relevance of the IBC cascade to human cystitis has been validated through two
independent lines of investigation. The rst
approach involved the analysis of multiple pairings of murine strains with clinical UPEC isolates to determine the prevalence of the IBC
developmental pathway in murine hosts with
various genetic backgrounds (34). The mouse
strains C57BL/6, CBA/J, FVB/NJ, C3H/HeN,
and C3H/HeJ all supported the development of
IBCs formed by UTI89 (human cystitis UPEC
isolate) and CFT073 (blood isolate of a patient with pyelonephritis). Additional isolates
from each of the four clinical forms of human UTI (i.e., acute cystitis, recurrent cystitis, pyelonephritis, and asymptomatic bacteriuria) also formed IBCs. The observation that
multiple human UPEC isolates and multiple
murine genetic backgrounds support IBC formation during cystitis indicates that this developmental pathway is not unique to a single UPEC/host pair. A second and more convincing approach entailed the identication
of exfoliated pods in urine specimens from
women seeking treatment for UTI (81). The
authors also identied lamentous bacteria in
41% of these urine samples, demonstrating that

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bacterial lamentation occurs commonly during human cystitis. Taken together, this evidence argues that the stages of the UPEC IBC
pathway observed in the murine model recapitulate human cystitis.
Evidence for the IBC pathway can also be
demonstrated in the urine of women infected
with other uropathogens (81). Filamentous
bacteria were observed in urine samples from
women infected with Enterobacter aerogenes,
Klebsiella pneumoniae, or Proteus mirabilis (81),
indicating that lamentation is a common
phenotype for gram-negative bacteria causing
disease in the urinary tract. Type 1piliated K.
pneumoniae primarily infects the urinary tract,
causing about 5% of community-acquired
UTIs. K. pneumoniae displays both differentiation branches of the IBC pathway during
infection, in a manner indistinguishable from
UPEC (82). Thus, the observations made for
UPEC using the murine model for human
cystitis not only hold true for translation to
the human disease, but also apply to other
gram-negative uropathogens.
Pyelonephritis is an ascending infection that
requires the migration of bacteria through the
vast length of the ureter, against the ow of
urine. It seems unlikely that UPEC ascension
would occur in the absence of interaction with
the ureteral epithelium. However, very little is
known regarding the events between bladder
colonization and the subsequent development
of pyelonephritis. Moreover, little is known regarding the interbacterial interactions that occur in the kidney or the primary niche for bacterial expansion. Given the propensity for biolm
formation during diseases caused by multiple
organisms, and the ability of pyelonephritic
strains to form IBCs in the bladder (34), it is
possible that biolm formation is also important for pyelonephritis.
INNATE AND ADAPTIVE

RESPONSES TO URINARY
TRACT INFECTIONS
Most attention paid to immune defenses
in the mammalian bladder has been

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directed at innate responses, particularly

those initiated by the Toll-like receptor 4
(TLR4), which is responsive to lipopolysaccharide (LPS) of gram-negative bacteria. Early
observations that the murine C3H/HeJ strain
was more susceptible to UTI (as measured by
colony-forming units recoverable from bladder
and kidneys) (35) were followed closely by the
identication of a mutation in the Tlr4 gene
in these mice (76, 104). Stimulation of TLR4
activates the NF-B signaling pathway via
MyD88, IL receptor-associated kinase, and
other kinases in host epithelial and immune
effector cells, leading to the expression of IL-6
and IL-8, which are measurable in the urine of
mice and humans with UTI (38, 85). However,
recent data suggest a parallel pathway activated
by TLR4 that also results in IL-6 and IL-8
expression (96). In this cultured bladder
epithelial cell model, TLR4 stimulation by
E. coli LPS triggers an inux of Ca2+ to the
intracellular space, followed by an increase in
cyclic AMP (cAMP). Subsequently, the cAMP
response element binding (CREB) protein is
phosphorylated, which results in transcription
of IL-6 and IL-8. Using selective blockade
of these signaling cascades, Song et al. (96)
determined that activation of epithelial IL-6
secretion by E. coli might even be faster via the
CREB pathway than the canonical pathway.
On the basis of these and other observations,
and given that IL-8 is an important chemoattractant for neutrophils, the defect in UTI resistance seen in C3H/HeJ (functionally TLR4decient) mice has been attributed primarily
to a failure to recruit neutrophils to the bladder upon UPEC infection (89). However, recent studies have revealed another novel role for
TLR4 signaling in host defense against infection of bladder epithelium. Invasion studies in
C3H/HeJ mice demonstrated 10-fold-higher
levels of intracellular bacteria (uropathogenic
E. coli or K. pneumoniae) 1 h postinfection, compared with C3H/HeN (TLR4 wild-type) mice
(94). Intracellular cAMP was observed to inhibit the activation of Rac-1, an intracellular element required for the cytoskeletal rearrangements that accompany bacterial invasion. Thus,
initial stimulation of TLR4 by bacterial LPS

might prime the supercial bladder epithelial
cells to be less receptive to invading pathogens.
Subsequently, these bladder epithelial cells can
also actively expel nascently invaded bacteria
in association with the exocytosis of fusiform
vesicles that accompanies bladder distension
(13) (Table 1). Additional RNA interference
data suggest that the exocytosis process is itself
TLR4 dependent (93).
The clinical relevance of TLR4- and IL-8mediated neutrophil recruitment to phenotypic
susceptibility to UTIs in humans has been suggested by several recent papers, leveraging advances in sequencing capacity. Svanborg and
colleagues (78) found that TLR4 expression on
neutrophils from children with asymptomatic
bacteriuria was lower than on neutrophils from
control children; there were accompanying differences in the expression of certain adaptor
proteins. Using a large cohort of families that
included children with a history of recurrent
UTIs, the same group also found that low
CXCR1 (IL-8 receptor) expression levels correlated with the incidence of acute pyelonephritis (60). Subsequently, CXCR1 mutations and
polymorphisms were identied in several patients with recurrent pyelonephritis (61). Although CXCR1 mutations were not correlated with pyelonephritis in a separate cohort
of Italian children, IL-8 gene polymorphisms
were found in this latter group (6). Correlated
with these observations, mice decient in IL8 receptor or the related chemokine receptor
CXCR2 (which recognizes IL-8 and other ligands) demonstrate increased susceptibility to
experimental UTI and urinary tractderived
bacteremia (97, 98).
In addition to LPS, other bacterial products
might stimulate TLR4 and other TLRs that
are produced by epithelial cells and/or resident
immune effectors of the urinary tract. Although type 1 pili promote bacterial adhesion
and invasion (which in turn facilitate LPS
recognition), there are also data indicating
that type 1 pili themselves, or the adhesive
tip protein FimH, stimulate TLR4 alone or
in concert with LPS (7, 9, 39). P mbriae
TLR: Toll-like
receptor
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also appear to stimulate TLR4, perhaps via a

ceramide intermediate (31). TLR2 is stimulated by peptidoglycan, as might be presented
by gram-positive uropathogens, including Enterococcus and Staphylococcus species, as well as by
lipoproteins and perhaps OmpA (44) of other
extraintestinal pathogenic E. coli. Mice lacking
TLR5, which responds to bacterial agellin,
permit higher bacterial loads in the bladder
and kidney following transurethral inoculation
(2). The murine receptor TLR11, associated
with a pseudogene in humans, also appears to
respond to uropathogenic bacteria (108). In a
recent case-control study of adult women with
a history of UTI in which TLR genes were examined, polymorphisms in TLR1, TLR4, and
TLR5 were correlated with protection from,
or susceptibility to, some UTI phenotypes (37).
Although susceptibility to UTI thus far appears to be related primarily to function of the
innate immune system, additional determinants
are likely important in this polygenic phenotype. For example, the increased susceptibility
of C3H/HeJ mice was recently suggested to
be due to at least two other loci in addition to
Tlr4 (41). Accelerating progress in genomic sequencing methodology might facilitate the elucidation of other contributing genes, but these
efforts may be hampered somewhat by the continuous, rather than discrete, nature of UTI susceptibility phenotypes in human populations.
Other mediators also shape the extent of
the polymorphonuclear leukocyte (PMN) response to infection. UPEC infection was recently demonstrated to induce the secretion of
granulocyte colony-stimulating factor (gCSF)
in the bladder, and antibody-mediated depletion of this cytokine reduced PMN inux
following UPEC infection (43). Similarly, plasminogen activator inhibitor type 1 (PAI-1) inuences cell migration through its effects on integrin binding; upon UPEC infection of mice
lacking PAI-1, kidneys bore signicantly higher
bacterial burdens and fewer PMN inltrates
than wild-type counterparts did (79). Perpetuation of the PMN response might be controlled
by cytokines such as IL-17, which has an emerging role in bridging innate to adaptive immunity

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Justice
(72) and is present at high levels in the bladder

at later time points following inoculation (T.
Nicholson & D. Hunstad, unpublished data).
Finally, the secretion of a number of soluble
antibacterial compounds into the urinary tract
is induced by UPEC infection. Among short
antibacterial peptides, the human cathelicidin
LL-37 is detectable in the urine during human cystitis, and mice decient in its ortholog
(CRAMP) demonstrate increased susceptibility
to UTI (18). UPEC infection also elicits the
production of nitric oxide in association with
upregulation of the iNOS gene (69). However,
UPEC may employ strategies to resist the antibacterial effect of nitric oxide, as mice decient in iNOS generally have shown no increased susceptibility to UTI (51, 75).
A more detailed knowledge of adaptive immune responses to UPEC is a prerequisite for
the development of next-generation candidate
vaccines for the prevention of UTI. A number
of vaccine antigens have been explored; these
were extensively reviewed earlier this year
(91) and are not enumerated here. Although
vaccines based on P or type 1 pilus components
have generated substantial mucosal antibody
responses, protection from subsequent infections has been incomplete, perhaps because
of phase variation in the expression of these
antigens during infection. More recently,
a variety of experimental approaches have
been applied to search for immunodominant
epitopes, revealing an array of new candidate
targets, several of which were iron acquisition
factors (90, 91).
IMMUNE EVASION STRATEGIES

OF UPEC
Given that provocation of innate responses results in secretion of proinammatory cytokines
and chemoattractants, resulting in an inux of
neutrophils that devour available pathogens,
it would stand to reason that UPEC might
possess strategies to delay, dampen, attenuate,
or subvert these responses, especially early in
infection. In fact, recent data demonstrate that
multiple such strategies are in play at various

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stages of the pathogenic cascade of bacterial

cystitis.
As detailed above, UPEC and other
uropathogens elicit inammatory responses via
TLR4 and other receptors on epithelial and
bladder-resident immune effector cells. However, several lines of evidence suggest that
UPEC, unlike laboratory or commensal strains
of E. coli, can at least partially suppress these
responses. UPEC stabilize IB, suppressing
NF-B activity in association with increased
bladder epithelial cell apoptosis upon exposure
to UPEC (53). Accordingly, multiple UPEC
strains elicit lower levels of IL-6 and IL-8
from uroepithelial cells (Table 2), compared
with laboratory strains, and can block secretion
of these cytokines upon co-inoculation with
known NF-B stimuli (11, 42). Genes involved
in LPS biosynthesis (e.g., rfa and rfb genes and
waaL) are important for the phenotype, suggesting that alteration in LPS structure may
in part underlie the nonstimulatory properties
of UPEC (12, 42). Lack of the OMP chaperone SurA also abrogates the suppressive phenotype (42); perhaps reduced levels of the SurAdependent LPS transport protein LptD (103)
alter the presentation of such a nonstimulatory
LPS. However, LPS differences alone do not
account for cytokine suppression (40), suggesting that additional UPEC anti-inammatory
strategies are active.
Recently, the UPEC strain CFT073
was found to encode a Toll/IL-1 receptor
domain-containing protein, termed TcpC,
that interacts with the host adaptor protein
MyD88 to inhibit downstream TLR signaling
(19). Loss of this protein in UPEC led to
decreased bacterial burden in kidneys and
a reduction in histologically evident renal
damage, demonstrating the importance of
this protein in the pathogenesis of upper-tract
disease. TcpC-like genes were found in 40% of
clinical pyelonephritis isolates and in smaller
minorities of UPEC causing cystitis and
asymptomatic bacteriuria (19), again indicating
that additional, unidentied UPEC factors interfering with host proinammatory signaling
are likely to exist. The pathogenic importance
of UPECs anticytokine effect in cystitis might

lie in permitting the initial establishment of
infection, as suggested by a recent translational
study showing an absence of urinary IL-6 and
IL-8 secretion immediately preceding and
at the onset of symptomatic UTI in women
(21). Alternatively, UPEC might leverage
such a strategy in maintaining a chronic
presence within bladder epithelial cells without
attracting immune attention (see below).
In addition to suppressing proinammatory cytokine production from epithelial cells,
UPEC exposure leads to relative downregulation of neutrophil genes involved in inammatory signaling and in neutrophil chemotaxis, adhesion, and migration (J. Loughman &
D. Hunstad, unpublished data). These phenotypes may be important in delaying neutrophil
inux during very early stages of infection,
when the intracellular foothold is being established. Further, many UPEC strains encode cytotoxic necrotizing factor 1, which is delivered
to PMNs via outer membrane vesicles and modulates chemotactic activity by constitutively activating neutrophil Rho GTPases (22, 23).
Despite efforts by UPEC to forestall the
arrival of host immune effectors, the infected
bladder becomes heavily inltrated by leukocytes (especially neutrophils) that aggressively
seek and destroy the pathogen. These arriving
defenders mobilize rapidly across the luminal
surface of the bladder following establishment
of cystitis and are readily detected in the urine
of patients with UTI. Given that UPEC can
accomplish successful infection in the bladder
and/or kidneys (with a relatively low presumed
inoculum in human UTI) in the face of these defenses, it is reasonable to consider that UPEC
take steps to resist the antimicrobial activities
of neutrophils. Compared with nonpathogenic
E. coli, UPEC strains are less susceptible to
neutrophil killing in vitro and induce a less
robust production of reactive oxygen species
( J. Loughman & D. Hunstad, unpublished
data). Resistance to oxidative mediators is dependent in part on the activity of zinc uptake
in UPEC (84), while OMPs may be important
in resisting the effects of antibacterial peptides
213

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Quiescent
intracellular
reservoir (QIR): the
stationary phase of
UPEC within Lamp
1-positive vesicles in
the transitional and
supercial bladder
epithelial cells
following exfoliation
and regeneration of
the supercial facet
cells
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secreted by PMN and other host cells in response to UPEC infection (K. Watts & D.
Hunstad, unpublished data).
As detailed above, epithelial invasion and
IBC formation also represent a critical initial
strategy, providing a haven for bacterial multiplication. By video microscopy, PMNs can be
observed readily engulng numerous luminal
bacilli within hours of infection in the mouse
model. Meanwhile, bacteria that have successfully invaded and remained within epithelial
cells are sheltered from this attack; although
pods remain intact, PMNs locate these infected
epithelial cells but cannot access the expanding bacterial population (46). Mature IBCs also
yield a population of organisms that assume a
lamentous morphology and subsequently traverse the luminal surface. These long bacteria
resist PMN phagocytosis; as viewed by video
microscopy in murine cystitis, they withstand
direct contact with PMNs as nearby bacteria
with standard bacillary shapes are readily engulfed (49).
Elongated shape alone does not seem to confer protection, as UPEC made lamentous by
in vitro exposure to mitomycin C can be engulfed (49), as are other organisms (such as
fungal hyphae) that are larger in one or more
dimensions than mammalian PMNs (47). Filamentation is a common mechanism for survival of marine bacteria from predation by unicellular protists (73). Moreover, Champion &
Mitragotri (16) recently showed that phagocytosis of model particles was shape and size independent, except in the case of worm-shaped
particles (ca. 1 10 m). For worm-shaped
particles, local geometry at the initial point of
contact between phagocyte and particle dictated the outcome of these interactions: Phagocyte contact with the particle pole resulted in
productive phagocytosis, whereas all other interactions were nonproductive (16). The resistance of engulfment of lamentous UPEC
by phagocytes is also driven by local geometric interactions (D. Horvath & S. Justice, unpublished data). These observations strongly
suggest that lamentation of the pathogen is
a concerted response to host pressures; characHunstad
Justice
terization of transcriptional changes associated

with the lamentous stage would greatly elucidate our understanding of PMN resistance
by UPEC. Analogous lamentation programs
might also be employed by other gram-negative
pathogens (47).
ESTABLISHMENT OF THE
QUIESCENT INTRACELLULAR
RESERVOIR
As a result of apoptosis, the supercial epithelial
cell is released from the underlying transitional
layer and lost through micturition, either as an
intact pod (81) or as cellular debris. However,
this exfoliation response is not limited to pods
but eventually involves most or all of the supercial layer, exposing the underlying transitional epithelium (Figure 1). Unlike other epithelial layers of the body that completely turn
over in days, the uninfected bladder epithelium
may take months for complete replacement of
its outermost cell layer (45). In contrast with
this normal pace of turnover, the exfoliation
that follows UPEC infection in mice dramatically activates differentiation machinery, so that
a new supercial layer is regenerated within
days (66, 69). Along these lines, experimental
UPEC infection might be a useful tool to study
and modulate normal developmental processes
in the urothelium.
Although loss of the supercial facet cells
(particularly those containing IBCs) might favor termination of the acute infection, it sets
the stage for the establishment of a quiescent
intracellular reservoir (QIR) that has characteristics of a latent infection. In contrast to initial invasion of supercial facet cells, where a
fraction of invaded bacteria become free within
the cytoplasm, the organisms that invade the
transitional cells remain in a membrane-bound
compartment (Figure 2d) (68) and do not exhibit intracellular growth (46). As the transitional cells form syncytia in the new supercial facet cell layer, the QIR remains intact. In
mice, these bacteria persist for months following introduction of UTI (67), resist systemic
antibiotic therapy, and can serve as the source

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for recurrent UTIs in the absence of reinoculation of the bladder (86). Although exfoliated
pods and lamentous bacteria are readily identiable in the urine during UTI in humans, direct
evidence of QIR formation in women is lacking. An innovative approach to this question is
needed: Cystoscopy of women with active or recent UTI is generally contraindicated, and even
if tissue examination or sampling in this situation were feasible, locating the relatively few
cells harboring QIR bacteria presents a major
obstacle.
Host innate and adaptive immune systems
do not appear to recognize or eradicate QIR
bacteria in mice, further supporting the notion that the QIR represents a latent infection. Whether the bacteria have simply adopted
a truly quiescent existence, remaining below
the radar of the host in this niche, or whether
UPEC in the QIR are actively suppressing host
detection mechanisms (as suggested by the in
vitro models outlined above) is an open and
important question. An understanding of bacterial activities within this reservoir will inform
new avenues for eradication of these organisms,
which may signicantly effect the clinical problem of recurrence.
SUMMARY AND
FUTURE PROSPECTS
Recent years have seen an abundance of new information about what uropathogenic bacteria,
particularly E. coli, are doing in the urinary tract.
Although in many cases we also have begun to
understand how UPEC accomplish these steps,
further exploration of the mechanisms of pathogenesis is still needed. Areas of particular interest include the host-pathogen interplay during the initiation of infection. The balance of
bacterial invasion and expulsion may strongly
inuence the outcome of this encounter, and
the pathways involved might be pharmacologically manipulable. In addition, understanding

the immune evasion strategies of UPEC, the
pathogenic functions of lamentous bacteria,
and the biological basis of chronic bacterial persistence within the bladder will provide highvalue targets for new translational approaches.
This need is amplied by recent increases in the
prevalence of antibiotic-resistant organisms. As
therapeutic options become limited, knowledge
of pathogenic mechanisms in many bacterial infections will be needed to inform development
of antivirulence therapies that may curtail infection while applying less selective pressure on
pathogenic bacteria.
The proposal of an alternative mechanism
for recurrent cystitis is of clinical signicance
on at least two levels. First, the urine is sterile during latent UPEC infection. Therefore,
urine cultures do not always accurately reect
the bacteriologic status of the bladder (and
perhaps the upper urinary tract), and negative
urine cultures following antibiotic treatment
might not signify eradication of uropathogens.
Second, contemporary approaches to recurrent UTIs, including advice on hygienic practices and interventions such as the topical application of antimicrobials to the perineum,
have been inadequate to conquer the troubling problem of recurrence. The insights summarized here may serve to redirect the focus
from reinoculation of fecal bacteria toward control or elimination of latent bacteria residing
in the bladder. Although still emerging, these
new paradigms should already impact clinical thinking about antimicrobial therapy and
prophylaxis for recurrent UTIs. The potential for future basic and translational advances
directed at UPEC in the intracellular niche
is bounded only by the limits of our knowledge of this newly described lifestyle of the
uropathogen.
SUMMARY POINTS
1. UPEC are the predominant cause of community-acquired and healthcare-associated
UTIs.
215
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2. Distinct sets of virulence attributes equip UPEC strains for infection of the bladder or
kidney.
3. Mutations in TLR4 or IL-8 receptors have been identied in several kindreds with
recurrent pyelonephritis.
4. A subset of UPEC internalized into supercial bladder epithelial cells replicate within
the cytoplasm to form IBCs.
5. Filamentous UPEC emanate from IBCs and resist phagocytic clearance during extracellular movement across the luminal surface.
6. UPEC employ multiple strategies to downregulate proinammatory signaling and leukocyte activities during UTI.
7. UPEC can establish a chronic reservoir state within bladder epithelium, from which the
pathogen may reemerge to cause recurrences of cystitis.
DISCLOSURE STATEMENT
The authors are not aware of any afliations, memberships, funding, or nancial holdings that
might be perceived as affecting the objectivity of this review.
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Contents

Volume 64, 2010
Conversations with a Psychiatrist

L. Nicholas Ornston p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Vaccines to Prevent Infections by Oncoviruses
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TonB-Dependent Transporters: Regulation, Structure, and Function
Nicholas Noinaj, Maude Guillier, Travis J. Barnard, and Susan K. Buchanan p p p p p p p p p p p43
Genomes in Conict: Maintaining Genome Integrity During Virus
Infection
Matthew D. Weitzman, Caroline E. Lilley, and Mira S. Chaurushiya p p p p p p p p p p p p p p p p p p p p61
DNA Viruses: The Really Big Ones (Giruses)
James L. Van Etten, Leslie C. Lane, and David D. Dunigan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p83
Signaling Mechanisms of HAMP Domains in Chemoreceptors and
Sensor Kinases
John S. Parkinson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 101
Viruses, microRNAs, and Host Interactions
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Basis of Virulence in Community-Associated Methicillin-Resistant
Staphylococcus aureus
Michael Otto p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 143
Biological Functions and Biogenesis of Secreted Bacterial Outer
Membrane Vesicles
Adam Kulp and Meta J. Kuehn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 163
Structure, Function, and Evolution of Linear Replicons in Borrelia
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Intracellular Lifestyles and Immune Evasion Strategies of
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Bacterial Shape: Two-Dimensional Questions and Possibilities
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vi
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Organelle-Like Membrane Compartmentalization of Positive-Strand

RNA Virus Replication Factories
Johan A. den Boon and Paul Ahlquist p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 241

Noise and Robustness in Prokaryotic Regulatory Networks

Rafael Silva-Rocha and Vctor de Lorenzo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 257
Genetic Diversity among Offspring from Archived Salmonella enterica
ssp. enterica Serovar Typhimurium (Demerec Collection): In Search
of Survival Strategies
Abraham Eisenstark p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 277
Letting Sleeping dos Lie: Does Dormancy Play a Role in Tuberculosis?
Michael C. Chao and Eric J. Rubin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293
Mechanosensitive Channels in Microbes
Ching Kung, Boris Martinac, and Sergei Sukharev p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 313
Mycobacteriophages: Genes and Genomes
Graham F. Hatfull p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 331
Persister Cells
Kim Lewis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 357
Use of Fluorescence Microscopy to Study Intracellular Signaling in
Bacteria
David Kentner and Victor Sourjik p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 373
Bacterial Microcompartments
Cheryl A. Kerfeld, Sabine Heinhorst, and Gordon C. Cannon p p p p p p p p p p p p p p p p p p p p p p p p p p p p 391
Mitochondrion-Related Organelles in Eukaryotic Protists
April M. Shiett and Patricia J. Johnson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 409
Stealth and Opportunism: Alternative Lifestyles of Species in the
Fungal Genus Pneumocystis
Melanie T. Cushion and James R. Stringer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 431
How to Make a Living by Exhaling Methane
James G. Ferry p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 453
CRISPR/Cas System and Its Role in Phage-Bacteria Interactions
Hel`ene Deveau, Josiane E. Garneau, and Sylvain Moineau p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 475
Molecular Insights into Burkholderia pseudomallei and Burkholderia
mallei Pathogenesis
Edouard E. Galyov, Paul J. Brett, and David DeShazer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 495
Unique Centipede Mechanism of Mycoplasma Gliding
Makoto Miyata p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 519
Contents
vii
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Bacterial Sensor Kinases: Diversity in the Recognition of

Environmental Signals
Tino Krell, Jesus
Lacal, Andreas Busch, Hortencia Silva-Jimenez,
Mara-Eugenia Guazzaroni, and Juan Luis Ramos p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 539
Iron-Oxidizing Bacteria: An Environmental and Genomic Perspective
David Emerson, Emily J. Fleming, and Joyce M. McBeth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 561

Fungi, Hidden in Soil or Up in the Air: Light Makes a Difference

Julio Rodriguez-Romero, Maren Hedtke, Christian Kastner, Sylvia Muller,
and Reinhard Fischer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 585

Index
Cumulative Index of Contributing Authors, Volumes 6064 p p p p p p p p p p p p p p p p p p p p p p p p p p p 611
Errata
An online log of corrections to Annual Review of Microbiology articles may be found at
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Intracellular Lifestyles and

Annu. Rev. Microbiol. 2010. 64:20321

First published online as a Review in Advance on

urinary tract infection, epithelium, biolm, community, neutrophil

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Paradigms in the pathogenesis of urinary tract infections have shifted

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URINARY TRACT INFECTIONS . .

URINARY TRACT INFECTIONS

UTI: urinary tract

strain as that causing the initial infection (83).

it can be difcult to ascertain specic bacterial

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Host factors implicated in UPEC internalizationa

References are given in parentheses.

www.annualreviews.org Pathogenic Lifestyles of UPEC

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accumulation of urine. As a further result of

Regardless of the mechanism, this cytoplasmically located subpopulation of UPEC is

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Annu. Rev. Microbiol. 2010.64:203-221. Downloaded from www.annualreviews.org

of unorganized bacillary forms. Being located

Annu. Rev. Microbiol. 2010.64:203-221. Downloaded from www.annualreviews.org

with an asynchronous distribution. With typical

cis-trans peptidyl prolyl isomerase, SurA,

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INNATE AND ADAPTIVE

Annu. Rev. Microbiol. 2010.64:203-221. Downloaded from www.annualreviews.org

directed at innate responses, particularly

initial stimulation of TLR4 by bacterial LPS

also appear to stimulate TLR4, perhaps via a

Annu. Rev. Microbiol. 2010.64:203-221. Downloaded from www.annualreviews.org

(72) and is present at high levels in the bladder

IMMUNE EVASION STRATEGIES

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stages of the pathogenic cascade of bacterial

of UPECs anticytokine effect in cystitis might

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terization of transcriptional changes associated

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the pathways involved might be pharmacologically manipulable. In addition, understanding

Annu. Rev. Microbiol. 2010.64:203-221. Downloaded from www.annualreviews.org

Annu. Rev. Microbiol. 2010.64:203-221. Downloaded from www.annualreviews.org

Annu. Rev. Microbiol. 2010.64:203-221. Downloaded from www.annualreviews.org

Annu. Rev. Microbiol. 2010.64:203-221. Downloaded from www.annualreviews.org

Annu. Rev. Microbiol. 2010.64:203-221. Downloaded from www.annualreviews.org

www.annualreviews.org Pathogenic Lifestyles of UPEC

Annu. Rev. Microbiol. 2010.64:203-221. Downloaded from www.annualreviews.org

Volume 64, 2010

Conversations with a Psychiatrist

Organelle-Like Membrane Compartmentalization of Positive-Strand

Annu. Rev. Microbiol. 2010.64:203-221. Downloaded from www.annualreviews.org

Noise and Robustness in Prokaryotic Regulatory Networks

Bacterial Sensor Kinases: Diversity in the Recognition of

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Fungi, Hidden in Soil or Up in the Air: Light Makes a Difference

and Reinhard Fischer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 585

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