Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology (MIG), Lund University, Lund, Sweden, and The Wright Flemming Institute, Imperial College School of Medicine, London, England
Correspondence: Catharina Svanborg, Department of Laboratory Medicine, Division of MIG, Lund University, Sölvegatan 23, 223 62 Lund, Sweden. E-mail: catharina.svanborg{at}mig.lu.se
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Key Words: urinary tract infection • bacterial virulence factors • neutrophil migration • innate immunity • chemokines
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 View larger version (39K): [in a new window] |
Figure 1. The two-step model for neutrophil recruitment and mucosal
inflammation. Signal 1: bacterial attachment to mucosal cells activates
a first inflammatory response. The adhesin receptor interaction may
trigger different signal transduction pathways, depending on the
receptor specificity and the signaling properties of the receptor
molecule. Furthermore, attachment delivers other virulence factors to
the tissues. These include toxins, invasins etc. The figure illustrates
this concept for P fimbriae that bind to glycolipid receptors and
recruit TLR4 as coreceptors. Signal 2: the released proinflammatory
mediators constitute the second inflammatory signal. Chemokines recruit
inflammatory cells, and chemokine receptors direct cellular interaction
with the mucosal barrier. Inflammation is enhanced by the different
mediators released from the recruited cells, and subsequent steps in
the inflammatory process determine the balance between health and
disease. We propose that patients with UTI can be assigned into
different groups depending on the magnitude of these two signals.
"High responders" are the patients in whom inflammation occurs most
readily. The high-responder individual has a very active signal 1 and
signal 2, constituting the basis for symptomatic disease. If the
inflammatory response is fully functional, the patient may develop
transient symptoms but rapidly clears the infection. Individuals with a
high but dysfunctional response develop severe acute infection, and
chronic tissue pathology may result. "Low responders" do not
activate signal 1, due to genetic or reactive unresponsiveness, and
remain apparently refractory to the bacteria. They resemble the
Tlr4-deficient mice, in which infection establishes without triggering
an inflammatory response, and may become asymptomatic carriers.
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/ß, TCR
/
and RAG knockout mice [2
],
suggesting that specific lymphocyte populations do not contribute to
the defense. In contrast mouse strains with inherited or induced
neutrophil response defects are highly susceptible to infection and
develop symptomatic diseases or asymptomatic bacterial carriage.
C3H/HeJ mice (Tlr4-) are highly susceptible to
experimental UTI [3
], and these mice show a defective
neutrophil response to infection [4
]. Neutrophil
depletion renders normal mice as susceptible to UTI as C3H/HeJ mice
[5
], confirming the importance of neutrophils for
defense. Still, the C3H/HeJ mice remain asymptomatic, and there is no
evidence of tissue damage despite the large bacterial numbers in
kidneys and bladders, suggesting that the signaling pathways involved
in the inflammatory response are defective in these mice. Furthermore,
the results implicate that additional neutrophil response defects might
account for other aspects of disease. These observations stimulated us to study (1) mechanisms by which bacteria do trigger mucosal inflammation and (2) molecular interactions of neutrophils with urinary tract mucosa.
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 View larger version (89K): [in a new window] |
Figure 2. Chemokine response to E. coli infection of the human
urinary tract mucosa. (a) Biopsy specimens were obtained from the human
urinary tract and were exposed to uropathogenic E. coli in
vitro. The increase in epithelial-cell IL-1, IL-6, and IL-8 content was
detected by immunohistochemistry using monoclonal antibodies. For IL-8
a biphasic pattern was observed. First, preformed IL-8 was secreted,
then new IL-8 was synthesized and secreted. (b) mRNA repertoire
of uroepithelial cells after in vitro infection with E.
coli strains differing in fimbrial expression. The fimbriae were
shown to influence the chemokine repertoire of the cells.
pap+, prs+, P-fimbriated transformants;
pap-, E. coli K-12 host strain not expressing P
fimbriae; fim+, type 1 fimbriated; fimH-,
deletion in the fimH gene. fim-, E. coli
K-12 host strain not expressing type 1 fimbriae._art>
|
Attachment promotes inflammation by two general mechanisms. The bacteria may themselves activate the target cells through receptor-determined pathways [10 ] or deliver other virulence factors [11 12 13 ] in a molecular context that allows them to trigger a host response. Evidence for direct cell activation by fimbria-receptor interaction has been obtained for P and type 1 fimbriae. Both lectins mediate attachment to uroepithelial cells and stimulate an epithelial cytokine response, but they recognize different glycoconjugate receptors and activate different transmembrane signaling pathways. P fimbriae bind glycolipid receptors and activate the epithelial cells via a ceramide- and TLR4-dependent signaling pathway [10 13 ]. Type 1 fimbriae bind mannosylated glycoproteins on a variety of cells including neutrophils, but the signaling mechanism(s) involved in epithelial cell activation is not understood [14 ].
P-fimbriated Escherichia coli trigger
mucosal chemokine responses
P fimbriae bind to glycosphingolipid (GSL) receptors in the
uroepithelial cells [15
]. The receptor specificity is
defined by the oligosaccharide portion of the GSLs and specifically by
a Gal1-4Galß disaccharide motif [15
]. The receptor
GSLs lack a transmembrane domain but are bound to ceramide in the outer
leaflet of the lipid bilayer [16
]. P-fimbriated E.
coli stimulate an increase in intracellular ceramide levels with a
simultaneous decrease in surface-expressed receptor-active GSLs,
suggesting that ceramide is released by hydrolysis of the receptor
itself [10
, 17
]. Release and
phosphorylation of ceramide are detected within a few minutes after
exposure to P-fimbriated E. coli and the signaling involved
Ser/Thr protein kinases, because chemokine responses to P-fimbriated
E. coli are blocked in the presence of Ser/Thr protein
kinase inhibitors [10
]. This signaling pathway is
selectively activated by P fimbriae, because isogenic E.
coli strains expressing fimbriae with another receptor specificity
fail to release ceramide [10
14
].
P fimbriae recruit TLR4 as
coreceptors in cell signaling
Toll receptors and especially TLR4 are important for host
cell recognition of microbial molecules like lipopolysaccharide (LPS)
(Fig. 3
). A role for TLR4 in mucosal responses to P-fimbriated bacteria
was suspected from early studies in C3H/HeJ mice, which fail to respond
to experimental UTI [3
4
5
]. The TLR4- mice
produce a signaling-deficient form of the TLR4 protein and are found to
be completely unresponsive to infection with P-fimbriated E.
coli. Yet they respond to isogenic E. coli strains
expressing fimbriae with another receptor specificity, suggesting that
the P fimbriae target critical aspects of the TLR4-dependent signaling.
In vitro studies have show that human uroepithelial cells express
several TLR species, but only TLR4 expression is enhanced by
P-fimbriated strains. By confocal microscopy, TLR4 was shown to
colocalize with the GSL receptors recognized by P fimbriae and to be
located in caveoli. We propose that P fimbriae first bind to the GSL
receptors and then recruit TLR4s as coreceptors in signal transduction
[13
].
 View larger version (28K): [in a new window] |
Figure 3. TLR4 activation in macrophages and epithelial cells may involve
different primary receptors. (a) LPS from gram-negative bacteria like
the uropathogens activates macrophages (MØ) via the CD14 receptor. LPS
bound to LPS-binding protein (LPB) is catalytically transferred to
CD14, and subsequently TLR4 is recruited as a coreceptor for signal
transduction. (b) The human urothelium is CD14 negative, and
uroepithelial cells respond poorly to soluble LPS. Still, chemokine
responses are triggered by uropathogenic bacteria, and this process is
enhanced by the fimbriae. Nonfimbriated bacteria are less
virulent and fail to deliver an activating signal to the cells. (c) P
fimbriae first bind their GSL receptor and then recruit TLR4 for
transmembrane signaling and cell activation. In this way they overcome
the LPS refractoriness of the uroepithelial cells, and activate a
chemokine response._art>
|
The host response induction by P fimbriae implicates a role for LPS because LPS is the only established agonist of the TLR4 pathway. Several observations have suggested that this is not the case in our model. The uroepithelial cells are CD14 negative and do not become activated by free LPS even in the presence of human serum. They respond to whole bacteria and secrete chemokines, but these responses are not inhibited by molecules like polymyxin B or bactericidal/permeability-increasing protein, which inactivate LPS in other systems [10 , 13 , 14 ]. Furthermore, inactivation of the endotoxic activity of lipid A in whole bacteria by mutation of the msbB sequences did not change the response to P-fimbriated bacteria.
The results suggest that the P fimbriae utilize an LPS-like cell activation mechanism in cells that lack CD14 and are refractory to LPS itself [13 ]. It thus appears that the GSL receptors on epithelial cells serve a function similar to that of CD14 on macrophages. Whereas LPS targets TLR4 via CD14, the P fimbriae may activate TLR4 via their GSL receptors. In this way they overcome the mucosal LPS barrier that normally controls inflammation (Fig. 3) .
Furthermore, findings illustrate how the receptor specificity of the fimbriae and the nature of their cell surface receptors influence the transmembrane-signaling pathways involved in chemokine activation. As a consequence, fimbriae may be expected to direct the repertoire of cytokines expressed by infected epithelial cells. Bacteria "play" on the host response repertoire, through the receptor specificity of their adhesins, and thus activate different aspects of the host response repertoire.
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Figure 4. IL-8 and CXCR1 are involved in transepithelial neutrophil
migration (a). Epithelial cell layers in transwell inserts were
stimulated for 24 h with uropathogenic E. coli in the
lower well, neutrophils were added to the upper well, and
transmigration was quantified after 3 h. The epithelial cells were
found to increase their expression of IL-8 and of the CXCR1 and CXCR2
chemokine receptors. Antibodies to IL-8 or CXCR1 blocked neutrophil
transmigration, demonstrating the involvement of these molecules in
neutrophil-epithelial cell interactions (b). _art>
|
The in vitro data have largely been corroborated in vivo. Epithelial cells in the human urinary tract mucosa synthesize IL-8 [29 ], and a rapid increase in urine IL-8 concentrations occurs after intravesical infection of human patients [29 30 31 ]. In deliberately colonized patients, there is a strong correlation of urinary IL-8 levels with urinary neutrophil numbers, and anti-IL-8 antibodies reduce the in vitro neutrophil chemotactic activity of urine obtained from patients with UTI by 50% [31 ], supporting a role of IL-8 in the process of neutrophil recruitment [29 ].
In vivo studies in the murine UTI model have identified macrophage-inflammatory protein (MIP)-2 as an important IL-8 equivalent in the urinary tract [5 ]. Infection causes a rapid epithelial MIP-2 response; neutrophils are recruited, and antibodies to MIP-2 have been shown to block neutrophil migration across the barrier in vivo. Indeed, antibody treatment blocks their passage into the urine and causes the neutrophils to accumulate under the kidney and bladder epithelium, demonstrating that epithelial activation is essential and confirming the importance of chemokines like IL-8 for the movement of neutrophils in the peripheral compartment.
Influence of bacterial attachment on the epithelial chemokine
repertoire
Uropathogenic E. coli stimulate a wide range of
epithelial CXC (IL-8, GRO-, IP-10, MIG) and CC (MCP-1, MIP-1)
chemokines in addition to IL-8 [2
]. The epithelial
expression of IL-8 and MCP-1 mRNA increased rapidly after infection
with uropathogenic E. coli and declined after 24 h
(Fig. 2)
, suggesting that secretion of these two chemokines by
epithelial cells is more important during the acute inflammatory
response than during the chronic phase. The rapid kinetics of IL-8 and
MCP-1 mRNA production and secretion after E. coli infection
correlates well with the increased neutrophil influx into the urine
that is observed at the onset of UTI. One of the most important
proinflammatory functions of kidney epithelial cells might indeed be to
provide signals for inflammatory cells like neutrophils.
Fimbria-mediated attachment influences the chemokine response
repertoire [33
34
35
]. Type 1 fimbriated strains have been
shown to elicit mainly neutrophil-activating chemokines (e.g., IL-8 and
GRO-), whereas the P fimbriae trigger a chemokine repertoire
favoring the recruitment of many different cell types, including
lymphocytes and monocytes, in addition to neutrophils (e.g., MCP-1 and
MIP-1). For example, the early MCP-1 response may activate mast
cells, macrophages, monocytes, and even neutrophils as receptors for
MCP-1 are found on all of these cells [36
,
37
]. The involvement of these cell types in the chronic
inflammatory infiltrate of the kidney and bladder needs further study.
Epithelial chemokine receptor expression increases in response to
infection
IL-8 mediates its biological activity through the
G-protein-coupled receptors CXCR1 and CXCR2. Several cell types have
been shown to express CXCR1 and CXCR2, including endothelial cells
[37
], basophils [38
], dendritic cells
[39
], mast cells [40
], type 1 helper
cells [41
], and eosinophils [42
], but
these receptors have been most extensively studied on neutrophils. (For
review see 32.) Both CXCR1 and CXCR2 on neutrophils stimulate the
release of granule enzymes, exocytosis, and intracellular
Ca2+ mobilization, but the respiratory burst and activation
of phospholipase D depend exclusively on stimulation through CXCR1
[44
]. It should be noted that IL-8 mediates its effect
on neutrophil chemotaxis predominately through CXCR1, even though IL-8
can induce changes in chemotaxis and calcium concentration through
CXCR2 as well [32
, 40
41
42
43
44
45
46
47
48
].
We have shown that infection stimulates CXCR1 and CXCR2 expression also in human urinary tract epithelium. CXCR1 has been shown to play a crucial role in neutrophil migration across infected human uroepithelial cell layers in vitro [47 ], because anti-CXCR1 antibodies inhibit neutrophil migration, but anti-CXCR2 antibodies have no effect. These experiments suggest that CXCR1 is the essential receptor in this process.
Aberrant neutrophil migration in mIL-8Rh mice
The importance of the chemokine receptors for the mucosal
inflammatory response has been further studied in murine IL-8 receptor
knockout (mIL-8Rh KO) mice. Mice have a single functional receptor for
the chemokines homologous to IL-8. This murine IL-8 receptor homologue
(mIL-8Rh) shares 69% and 71% amino acid identity with the human IL-8
receptors CXCR1 and CXCR2, respectively [47
]. The
neutrophils of the mIL-8Rh KO mice fail to migrate in response to the
CXC chemokines but have intact sensitivity for other activation
pathways [49
].
The in vivo relevance of epithelial CXCR expression was confirmed in these mIL-8Rh KO mice. We subjected them to intravesical infection with uropathogenic E. coli and examined the neutrophil response in kidneys and bladders.The mice had an intact epithelial chemokine response, as determined by MIP-2 staining, and intact secretion of MIP-2 into the urine during the first hours after infection, showing that the IL-8 receptor deficiency did not influence the chemokine response per se [49 ]. With time, a difference in tissue distribution of MIP-2 was noticed compared with that in the control mice [50 ]. The MIP-2 response decreased in controls, but the mIL-8Rh KO mice continued to produce MIP-2, suggesting impaired down-regulation and/or continued stimulation of this response. The chemokine receptors may, indeed, be essential also to sequester the chemokine at the site of production.
The mIL-8Rh KO mice had a dysfunctional neutrophil response compared with the BALB/c controls. The defect was not mainly in neutrophil recruitment into the tissues but in the ability of these neutrophils to cross the epithelial barrier and to kill the bacteria. Even if the influx of neutrophils was somewhat delayed compared with that in the controls, the neutrophils did reach bladder and kidney tissue after about 24 h, showing that the chemotactic gradient was intact and that chemotactic signals not depending on the IL-8 receptor are involved in this process. These signals have not been identified.
In control mice, the neutrophil influx was transient, and the neutrophils crossed the epithelial barrier into the lumen, resulting in pyuria. In the mIL-8Rh KO mice, the neutrophils were unable to cross the epithelium into the lumen, resulting in low urine neutrophil numbers at all times. The neutrophils accumulated in large numbers under the epithelium and eventually filled the tissues. The results demonstrate that the epithelium forms a virtually impermeable barrier to the neutrophils in the absence of IL-8 receptors and that chemokines and chemokine receptors regulate the interaction of neutrophils with epithelial cells in vivo.
These experiments illustrate the compartmentalization of the signals and effector molecules involved in neutrophil migration. Apparently, the vessel wall and mucosal barrier present quite different challenges to the migrating neutrophil. Epithelial cells are the last to encounter the neutrophils on the way through the tissues, and thus they must have a different function than that of endothelial cells. The occurrence of CXCR1 and CXCR2 on endothelial cells is still controversial, and their function in neutrophil extravasation is unknown. Heparan sulfates and Duffy antigen receptors have been proposed to play a major role in IL-8 immobilization on the endothelial cell surface and neutrophil transendothelial migration [51 ]. Thus it appears that different molecular interactions may guide the neutrophils in the circulatory system or in the periphery, at the site of infection. The epithelial cells probably provide a more stable source of chemokines and may maintain their expression of chemokines and chemokine receptors longer than the endothelial cells. This may be essential to direct activated neutrophils away from the tissues.Mucosal surfaces may indeed be useful "burying grounds" where old neutrophils go to die.
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IL-8Rh KO mice develop renal scarring
Accumulation of neutrophils in the tissues of mIL-8Rh KO
mice results in tissue destruction, resembling renal scarring in humans
[51
]. After 7 days, control mice were healthy, and
infection was cleared, but mIL-8Rh KO mice had swollen kidneys with
neutrophil abscesses. After 35 days, they had developed kidney
pathology and renal scarring (Fig. 5
) [50
]. Fibrosis developed under the epithelium and
in the perivascular
space.
 View larger version (128K): [in a new window] |
Figure 5. Renal scarring in mIL-8 Rh KO mice. Kidneys were obtained
from the mIL-8 Rh KO mice 35 days after infection with
uropathogenic E. coli. Macroscopically they were pale,
small and with abscesses and fibrotic areas. By histology,
subepithelial and perivascular fibrosis was observed. a) Pelvic
epithelium. Arrows indicate fibrosis. b) Perivascular fibrosis. c) and
d) Neutrophil infiltration._art>
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IL-8Rh KO mice have a human
counterpart
There are considerable intraindividual differences in
the susceptibility to UTI and in the tendency to develop renal scarring
after acute pyelonephritis. Failure to resolve the local phase of acute
infection may cause renal scarring in children and lead to permanent
renal damage. The recurrence rate after a first episode of acute
pyelonephritis in children is estimated at between 30% and 40%. No
molecular explanations for the differences in disease susceptibility
have been offered.
The acute and chronic changes in the mIL-8Rh KO mouse closely resembled human disease and suggested that similar mechanisms might underlie the susceptibility in humans. This led us to examine CXCR1 expression in children with documented episodes of acute pyelonephritis. Twelve children were enrolled in the initial study and compared with 12 healthy age-matched controls with no history of UTI [49 ]. The neutrophil surface expression of CXCR1 was examined with a fluorescein-activated cell sorter, and the cells were inspected by confocal microscopy. Surface CXCR1 expression was lower and more heterogeneous in the patients. Furthermore, the CXCR1 mRNA expression in neutrophils was lower in the patients than in the controls. Despite the small number of patients, we found significant differences in receptor expression between patients and controls, suggesting that these differences are highly relevant. There was no evidence of a similar difference in CXCR2 expression.
Mutations in the CXCR1 gene
The low protein expression and the low mRNA levels
suggest that patients carry mutations that impair CXCR1 expression.
Both IL-8 receptor genes and a homologous pseudogene have been mapped
to position 2q34-35 in the human genome [52
53
54
]. This
region has been sequenced in patient and control DNA using primers for
the promoter region. Preliminary results are summarized in Figure 6
. We observed sequence heterogeneity in regions of the promoter
that are involved in transcription control. More extensive studies are
required to understand the disease implications of the observed
sequence variation.
 View larger version (25K): [in a new window] |
Figure 6. CXCR1 promoter sequences in patients and controls. The single copy of
the human CXCR1 gene has been mapped to chromosome 2q34-q35. Two
full-length sequences deposited in the data base were identical except
for two bases in the second exon. The gene consists of two exons
interrupted by an intron of 1.7 kb, and the entire orf
encoded in exon 2 [52
, 53
]. The 5' region
upstream of exon 1 encodes the promoter, and further upstream (-841 to
-280) potential silencer elements were identified. The CXCR1 promoter
has an SP-1 transcription start site. Studies of promoter activity in
transfected cells have identified PU.1 of the ets family of
transcription factors as a major regulator of the CXCR1 promoter. The
PU.1 binding motif is located at -7 to -4, and disruption of these
sequences inactivates transcription [54
]. The low CXCR1
mRNA expression in children with UTI suggests that the promoter might
carry mutations in regions that regulate transcription. Primers for the
entire promoter region were constructed based on the published
sequences. DNA was isolated from the patients and age-matched controls
and subjected to DNA sequencing. Polymorphic sites in patient and
control children are shown in the figure. We concluded that the CXCR1
promoter region is polymorphic. Studies aimed at quantifying the
promoter activity from patients and controls are ongoing.
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Neutrophils dominated in the inflammatory infiltrate of the urinary tract, and the urinary tract epithelium regulated the neutrophil response by secreting IL-8 and similar chemokines, which directed neutrophil migration across the mucosal barrier into the urine. Furthermore, infection enhanced the expression of the CXC chemokine receptors, which also are required for neutrophil migration across the epithelial barrier. mIL-Rh KO mice developed renal scarring when the recruited neutrophils failed to cross the barrier into the urinary tract lumen but accumulated under the epithelium.
The neutrophils played a crucial role in defense against infection. Normal mice had a transient neutrophil response, during which bacteria were eliminated from the tissues, but mice lacking a neutrophil response or having the defect exhibited by the mIL-8Rh KO mice failed to clear infection (Fig. 1) .
Finally, we found that patients with recurrent UTI had low expression of CXCR1 and that there were polymorphisms in the genes encoding these receptors. These studies provide a first molecular handle on the genetics of UTI. It is possible that discrete genetic defects underlie disease susceptibility in this patient group.
Received February 2, 2001; revised May 4, 2001; accepted May 4, 2001.
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rild, S., Martinell, J., Plos, K., Sandberg, T., Stenquist, K. (1988) Host-parasite interaction in the urinary tract J. Infect. Dis. 157,421-426[Medline]This article has been cited by other articles:
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