Pediatr Nephrol (2012) 27:2017–2029
DOI 10.1007/s00467-011-2089-1
REVIEW
Susceptibility to acute pyelonephritis or asymptomatic
bacteriuria: Host–pathogen interaction in urinary tract
infections
Bryndís Ragnarsdóttir & Catharina Svanborg
Received: 7 October 2011 / Revised: 30 November 2011 / Accepted: 2 December 2011 / Published online: 12 February 2012
# IPNA 2012
Abstract Our knowledge of the molecular mechanisms of
urinary tract infection (UTI) pathogenesis has advanced
greatly in recent years. In this review, we provide a general
background of UTI pathogenesis, followed by an update on
the mechanisms of UTI susceptibility, with a particular
focus on genetic variation affecting innate immunity. The
innate immune response of the host is critically important in
the antibacterial defence mechanisms of the urinary tract,
and bacterial clearance normally proceeds without sequelae.
However, slight dysfunctions in these mechanisms may
result in acute disease and tissue destruction. The symptoms
of acute pyelonephritis are caused by the innate immune
response, and inflammation in the urinary tract decreases
renal tubular function and may give rise to renal scarring,
especially in paediatric patients. In contrast, in children with
asymptomatic bacteriuria (ABU), bacteria persist without
causing symptoms or pathology. Pathogenic agents trigger
a response determined by their virulence factors, mediating
adherence to the urinary tract mucosa, signalling through
Toll-like receptors (TLRs) and activating the defence mech-
anisms. In ABU strains, such virulence factors are mostly
not expressed. However, the influence of the host on UTI
severity cannot be overestimated, and rapid progress is
being made in clarifying host susceptibility mechanisms.
For example, genetic alterations that reduce TLR4 function
are associated with ABU, while polymorphisms reducing
IRF3 or CXCR1 expression are associated with acute py-
elonephritis and an increased risk for renal scarring. It
should be plausible to “individualize” diagnosis and therapy
B. Ragnarsdóttir : C. Svanborg (*)
Institute of Laboratory Medicine, Section of Microbiology,
Immunology and Glycobiology (MIG), Lund University,
Sölvegatan 23,
22362, Lund, Sweden
e-mail: Catharina.Svanborg@med.lu.se
by combining information on bacterial virulence and the
host response.
Keywords Urinary tract infections . Bacterial virulence .
Host resistance . Genetic polymorphisms
Introduction
Bacteria often invade the urinary tract, but successful estab-
lishment of bacteriuria and infection is a much rarer event.
Not that urinary tract infections (UTIs) are rare—they are
among the most common bacterial infections in man and
important enough to be taken very seriously by physicians
in any type of practice [1].
Acute pyelonephritis (APN), a kidney infection with
local and systemic consequences, is the most severe form
of UTI. Patients experience flank pain, fever >38.5°C and
general malaise, and laboratory tests detect elevated levels
of circulating acute phase reactants [C-reactive protein
(CRP)] as well as evidence of local inflammation in the
urinary tract, such as pyuria and elevated cytokine levels
[2]. About 30% of adults with acute pyelonephritis develop
bacteremia, and urosepsis remains an important cause of
death.
Asymptomatic bacteriuria (ABU), defined by the pres-
ence of a large number of bacteria in the urine (>105 cfu/ml
urine), often for extended periods of time, without the ac-
companying symptoms of a UTI, is the other extreme of the
UTI spectrum [3–5]. ABU is also the most common form of
UTI, occurring in about 1% of girls, 2% of pregnant women
and 20% of both men and women above 70 years of age [3,
6–8]. Patients with ABU may develop a mild host response
that can be quantified in the urine, and after long-term
2018
carriage they may develop lymphoid follicles in the bladder
mucosa, which resolve after antibiotic therapy [9].
Acute cystitis is very common, yet not well defined. At
least half of all women experience at least once a sporadic
cystitis episode, accompanied by frequency, dysuria and
suprapubic pain. Treatment consists of antibiotic therapy,
but lower tract symptoms may also precede an upper urinary
tract infection, creating a grey zone between the groups with
symptomatic UTI [10].
So why do not all of us develop UTI daily when bacteria
accidentally gain access to the urinary tract? The answer is
to be sought in the properties of the bacteria; virulent uro-
pathogenic bacteria that cause acute pyelonephritis are for-
tunately not often represented in the perineal flora, except in
highly UTI-prone individuals who carry virulent bacterial
strains in their fecal/perineal flora for extended periods of
time. Furthermore, most hosts have an intact urine flow and
a highly efficient innate immune response that senses the
presence of invaders and destroys them, so that the urinary
tract can regain its sterility [11].
In this review, we focus on the determinants of bacterial
virulence factors and on host response dysfunction that
overrides the normally efficient defence and tilts the balance
towards inflammation, symptoms and disease.
Pathogenesis—an overview
Before invading the urinary tract, bacteria causing UTI often
reside for long periods in the intestinal flora. After spreading
via the perineum to the periurethral area, they ascend against
the urine flow and succeed in establishing bacteriuria facil-
itated by adhesion mechanisms, flagella-mediated motility
Fig. 1 Summary of the
symptoms and signs of urinary tract
infections (UTIs) and of correlating
bacterial virulence factors. Acute
pyelonephritis (APN) is a severe
infection of the kidneys that may
become life threatening if left
untreated. Asymptomatic
bacteriuria (ABU) results in a
symptom-free bacterial coloni-
zation of the bladder. The disease
severity reflects differences in
bacterial virulence, with APN
strains having multiple virulence
factors, such as P-fimbriae,
toxins and proteins such as TcpC
that inhibit an efficient innate
immune response. In contrast,
ABU strains lack many of the
virulence factors seen in APN
strains due to point mutations or
deletions
Pediatr Nephrol (2012) 27:2017–2029
and other adaptation strategies and by resistance to the many
and intricate antibacterial defense mechanisms that guard
the urinary tract against infection. Escherichia coli (E. coli)
bacteria cause 80–90% of community-acquired acute pyelo-
nephritis episodes and are especially common in children.
Less common infectious agents include Proteus mirabilis
and Klebsiella as well as Staphylococcus saprophyticus.
Nosocomially acquired infections may be caused by many
different organisms, depending on the hospital environment
and underlying host factors [10].
The subset of E. coli strains that causes acute pyelone-
phritis in otherwise healthy hosts is designated as “uropa-
thogenic” [12] and defined by packages of chromosomal
virulence genes, forming so-called “pathogenicity islands”
(Figs. 1, 2) [13, 14]. The sequential activation of those genes
facilitates host tissue attack and bacterial survival. For ex-
ample, fimbriae initiate tissue attack through bacterial adhe-
sion to the mucosa [12] and increase tissue exposure to
secreted bacterial virulence factors, such as hemolysin and
lipopolysaccharide (LPS). Such toxins damage the tissues
by interfering with cellular functions or by directly inducing
cell death. The “uropathogenic” strains can be identified by
their surface antigen expression (OKH serotypes) or by
typing for virulence factors like P-fimbriae [12, 15, 16].
In recent years, cellular and molecular mechanisms that
define the antibacterial host defence system and the extent
of tissue damage have been extensively studied [17]. Early
studies in the murine UTI model (Fig. 3) as well as clinical
observations (Fig. 4) have clearly shown that resistance to
infection relies on innate immune mechanisms [18]. Defects
in innate immunity drastically increase UTI susceptibility,
both in mice carrying single gene deletions and in patients
prone to acute pyelonephritis or ABU (Table 1) [19–25]. In
Pediatr Nephrol (2012) 27:2017–2029 2019

Fig. 2 Schematic of the urinary

tract mucosal barrier and
immune cells involved in the
host response. Uropathogenic
Escherichia coli elicit a
complex innate immune
response leading to the
recruitment of inflammatory
cells and to the possibility of a
subsequent specific immune
response. In contrast,
asymptomatic carrier strains do
not elicit a significant innate
immune response and do not
trigger tissue inflammation.
Modified figure from
Ragnarsdóttir et al. [17] with
the permission of Nature
Reviews Urology. PMNs
Polymorphonuclear leukocytes

contrast, the defence against acute UTI does not rely on
specific immunity defined by antigen-specific lymphocyte
activation [26].
Bacterial virulence factors
Bacterial adhesion Adherence to cells in the urinary tract is
a critical step to initiate tissue attack [12, 27]. Mediated by
bacterial surface fimbriae that recognize specific receptors
on host cells, bacteria become associated with the uroepi-
thelial lining, and the adherent state facilitates the action of
toxins and invasion factors. Several fimbrial types may be
involved in the attachment process, and these are distin-
guished by their structural features as well as by the oligo-
saccharide sequences in host glycolipids or glycoproteins
that they recognize. Type l fimbriae bind to mannosylated
epitopes present in the Tamm–Horsfall glycoprotein, in
secretory immunoglobulin A (IgA), in bladder cell uropla-
kins or in integrin molecules [28–32]. S-fimbriae bind sialic
acid epitopes present in renal sialylated proteins and lipids
[33]. P-fimbriae recognize Galα1–4Galβ-epitopes in the
globoseries of glycolipids [34]. The expression of P-
fimbriae is strongly linked to virulence, being expressed
by about 80% of strains causing uncomplicated acute py-
elonephritis but in only <20% of children with ABU [35,
36]. The frequency of P-fimbriated strains is reduced in
patients with impaired resistance, such as pregnancy, urody-
namic defects or genetic abnormalities (see below).
Lipopolysaccharide Lipopolysaccharide is an endotoxin of
Gram-negative bacteria, with the lipid A anchored in the

Fig. 3 Innate rather than

adaptive immunity is essential
for bacterial clearance during
urinary tract infections (UTIs).
In the murine model, Tlr4−/− as
well as Myd88−/− and Trif−/−
mice develop asymptomatic
carriage while mCxcr2−/− and
Irf3−/− mice are highly
susceptible and associated with
severe disease and increased
mortality. Defects of the
specific immune response, in
contrast, did not increase
urinary tract infection (UTI)
susceptibility (T, B cell or RAG
mice) [18, 19, 25]
2020
Fig. 4 Polymorphisms in three human genes (TLR4, CXCR1 and
IRF3) have been associated with urinary tract infection (UTI) suscep-
tibility. Functional studies have confirmed their effect on gene expres-
sion. Single nucleotide polymorphisms (SNPs) that have been shown
to result in lower TLR4 promoter activity, in vitro, are -4038, -3612, -2081
and -2026. An SNP that has been shown to reduce CXCR1
outer membrane being responsible for the toxic effects.
Injection of lipid A mimics many of the symptoms associ-
ated with acute pyelonephritis, Gram-negative septicemia or
other serious Gram-negative infections, including fever and
activation of the acute phase response. In addition, LPS
carries an invariable oligosaccharide core and a repeating
oligosaccharide that determines the O antigen. LPS activates
Toll-like receptor 4 (TLR4) signalling, after binding to
soluble or cell surface-associated CD14, in conjunction with
MD2 [37, 38]. This mechanism is essential for innate im-
mune activation during systemic infection but is less impor-
tant at mucosal surfaces, where the cell-bound CD14
receptor is often missing [39, 40].
Capsular polysaccharide Capsular polysaccharides are
formed from oligosaccharide polymers. Different capsular
types are defined by their variant antigenic oligosaccharide
epitopes. The capsules surround bacteria in blood and tissues
and have been shown to contribute significantly to bacterial
survival in the presence of a functional host defense by coun-
tering lytic effects of complement and phagocytosis [41].
Mutant bacteria with genetically altered capsule expression
show reduced virulence in experimental UTI models [42].
Hemolysin Hemolysins are cytotoxic, pore-forming proteins
that permeate the cell membrane. They are commonly iden-
tified by their ability to lyse erythrocytes. Hemolysin pro-
duction was first observed in the 1940s in E. coli causing
acute pyelonephritis, and hemolysin have been found to
Pediatr Nephrol (2012) 27:2017–2029
expression in APN-prone patients is the intronic variant at position
G217C. The A/A-CC genotype for IRF3 promoter SNPs is associ-
ated with APN, resulting in lower IRF3 promoter activity. Modi-
fied figure from Ragnarsdóttir et al. [17] with the permission of
Nature Reviews Urology
occur more frequently in E. coli causing acute pyelonephri-
tis than in fecal isolates; however, the difference in frequen-
cy is less pronounced than that for P-fimbriae [43].
Metabolic competition Bacteria compete with the host for
many nutrients, including iron. Lactoferrins are synthesized
by the mucosa and transferrin is present in the circulation,
with concentrations increasing in response to infection [44].
Although no single iron uptake system is essential, all
uropathogenic strains express some form of iron uptake.
Enterobactin is expressed by nearly all E. coli strains, but
most E. coli strains causing acute pyelonephritis produce
aerobactin, which is a high-affinity iron-binding protein, as
well as other iron-sequestering proteins, such as yersinia-
bactin, ChuA and Iro [45–48].
Host response and the antibacterial defense
The innate immune response is activated in a pathogen-
specific way by P-fimbriae-mediated adhesion. Subsequent
cleavage of the glycolipid receptors releases ceramide,
which activates TLR4 signalling, and transcription factors
such as IRF3 trigger cytokine production and neutrophil
recruitment, which in turn kill the bacteria [25, 49–51].
These mechanisms also determine the symptoms and signs
of acute UTI. The loss of functional TLRs reduces the innate
immune response and promotes long-term bacterial
Pediatr Nephrol (2012) 27:2017–2029 2021

26, 52, 94]

TGF-β1, Transforming growth factor-beta1; TLR4, Toll-like receptor 4; SNP, single nucleotide polymorphism; UTR, untranslated region; PBMC, peripheral blood mononuclear cell; ABU,
[21, 22, 62]
[18, 23, 24,
colonization and ABU [18, 24, 52]. In contrast, dysfunc-

References

[95–98]
tional, exaggerated responses result in severe acute infec-

[25]
tions with inflammation (Fig. 5). The resulting defects in
antibacterial effector functions enable the infection to be-
come chronic, and rapid renal scarring occurs in animals
Disease association

with deficiencies in these pathways.

Renal scarring
TLR4 signalling activates the cytokine response in
infected uroepithelial cells, and secreted cytokines orches-
trate mucosal inflammation. Indeed, the presence of a mu-
ABU

APN
APN

APN cosal cytokine response was first observed in UTI. Interleukin

(IL)-6 is secreted by uroepithelial cells and acts as an endog-
enous pyrogen, activates hepatocyte CRP production and

SNPs to RS but no correlation between

PBMC TGF-β1 production was lower in
increased mRNA 3′-processing, reduced

stimulates mucosal B cells to produce IgA antibodies [53,

SNPs and circulating TGF-β1 levels

levels of the long CXCR1 transcript
and low innate response in patients.

Association of promoter and coding 54]. The biological activities of IL-6 thus agree with the
clinical presentation of acute pyelonephritis, and IL-6 is
promoter SNP heterozygotes

detected in the blood and urine of patients with acute pyelo-

Reduced promoter activity,

Reduced promoter activity

Reduced promoter activity

low TLR4 expression

nephritis. Several studies have suggested that urine cytokine

levels directly reflect the degree of renal involvement.
Biological effect

Infected epithelial cells also secrete IL-8, which is che-

motactic for neutrophils. IL-8 forms a gradient across
the mucosa, and neutrophils migrate towards the gradi-
ent and cross the mucosal barrier into the urine. The
concentration of IL-8 correlates with the number of
leucocytes in urine, and the chemotactic activity of
CXCR1 SNP in 3′ UTR region

urine is inhibited by IL-8 antibodies [27, 55]. In addi-

Genetic variants in humans

tion, infection increases the expression of IL-8 receptors,

IRF3 promoter (A/A-C/C)
TLR4 promoter SNPs/GP

which are important targets for the IL-8 family of che-

TGF-β1 promoter and
coding region SNPs
CXCR1 intronic SNP

mokines and support neutrophil migration and activation.

These mechanisms explain the classical phenomenon called
“pyuria”, i.e. the presence of leucocytes in urine, which has
Humans

been used as a sign of UTI since microscopy started to be used

for clinical diagnosis. More recently, a number of additional
chemokines have been found in urine, probably reflecting a
more complex immune response in the mucosa, especially
Acute infection and urosepsis. Extensive

from multifocal, mixed inflammatory

during long-term bacterial carriage [56].

Table 1 Genetic variation and urinary tract infection susceptibility

Mice with acute pyelonephritis have

infection and urosepsis. Extensive
Delayed neutrophil response. Acute

It is not clear if the urine flow, per se, is sufficient to

Uninfected TGF-β1−/− mice suffer
marked kidney cell expression

cell response, tissue necrosis,

maintain sterility. Clearly, the efficiency with which the

abscesses in surviving mice.

abscesses in surviving mice.

delayed bacterial clearance

urinary tract maintains sterility is aided by antibacterial

Low innate response and

organ failure and death

peptides that directly kill the bacteria (for review see [57]).
asymptomatic bacteriuria; APN, acute pyelonephritis
of TGF-β1 mRNA.

In an epidemiologic study of sensitivity to the human cath-

Biological effect

elicidin LL-37, APN strains were found to be more resistant

than lower urinary tract isolates [58]. The importance of
antibacterial peptides is evident in the murine model as well.
Mice have only one urinary tract cathelicidin, CRAMP
(cathelin-related, antimicrobial peptide), and knock-out
mice for this gene were more susceptible to UTI than
Genetically modified mice

wild-type mice [58].

(non-functional Tlr4)
Tlr4−/− or C3H/HeJ

Host factors predispose to UTI

mCxcr2−/−

TGF-β1
Irf3−/−

The frequency of UTI varies with age, gender and socio-

Mice

economic factors. The susceptibility to UTI is higher in

2022
Fig. 5 The P-fimbriae on uropathogenic E. coli are essential for the
activation of CD14-negative epithelial cells. P-fimbriae use the PapG
tip adhesin to bind oligosaccharide sequences in the globoseries of
glycosphingolipids. After binding, the receptors are cleaved, and the
release of ceramide triggers Toll-like receptor 4 (TLR4) signalling.
Defects in the TLR4 signalling pathway greatly affect the host immune
response and therefore disease outcome. Gene deletions in the green-
women than in men, except during the first year and at the
end of life. Still more noteworthy are the differences in UTI
susceptibility across these lines, however. Certain individu-
als develop severe, acute infections, some are likely to suffer
recurring UTIs and a subset develops a chronic state of
tissue damage, leading to renal scarring. Scientists have
been working for decades to better understand the factors
that determine susceptibility and to develop diagnostic tools
to discriminate these individuals from others who only expe-
rience sporadic UTI episodes. A number of genetic risk factors
have now been identified that distinguish pyelonephritis-
prone children from those who consistently develop ABU
(for a review, see [17]). Even if the information is still limited,
it is clear that genetic variation that particularly affects innate
immunity influences UTI susceptibility. These examples
show that the deletion of single genes with crucial functions in
Pediatr Nephrol (2012) 27:2017–2029
shaded area (Tlr4, Myd88 or Trif) protect against symptomatic infec-
tions, and infected hosts develop asymptomatic bacteriuria with no
evidence of tissue pathology. Gene deletions in the red-shaded area
(Irf3 or Ifnβ) exacerbate the severity of acute pyelonephritis, with
increased mortality, followed by rapid tissue damage. Modified figure
from Ragnarsdóttir et al. [17] with permission of Nature Reviews
Urology
innate immune signalling results in an immunodeficient phe-
notype, with increased UTI susceptibility in mice and poly-
morphisms in patients with different forms of UTI.
Predisposition to acute pyelonephritis is also influenced
by dysfunctional voiding or vesicoureteric reflux (VUR)
[59]. Patients with such dysfunctions have an increased
frequency of UTI and are susceptible to infection with
bacteria of lower virulence than patients with anatomically
normal urinary tracts [60].
Genetic variation and ABU susceptibility
The effects of a number of genetic risk factors and suscep-
tibility to UTIs are summarized in Table 1.
Pediatr Nephrol (2012) 27:2017–2029
Reduced TLR signalling and ABU As outlined above, the
activation of TLR signalling and the resulting production of
mediators of innate immunity, including cytokines/chemo-
kines, are crucial for the elimination of bacteria from the
urinary tract. Without TLR4, the production of antimicrobial
peptides is abrogated, and neutrophil recruitment is reduced,
as is their activation to engage in bacterial phagocytosis and
to recruit a second wave of inflammatory cells that are
needed to rid the tissues of debris from dying phagocytic
cells. Pharmacological or genetic inhibition of neutrophil
migration/activation has been shown to drastically impair
the antibacterial defense, resulting in poor bacterial clear-
ance and drastic tissue pathology [21, 61, 62]. Still, genetic
defects affecting TLR signalling seem to be protective
and mainly associated with ABU, suggesting that just
reducing the efficiency of bacterial clearance does not
create pathology—when the tissue inflammation that causes
the pathology is blocked. Mice lacking the Tlr4 gene devel-
op ABU, with >105 cfu/ml of bacteria, but no symptoms or
tissue damage. Lack of murine Tlr4 expression and the result-
ing absence of inflammation thus appear to be protective
rather than destructive [18, 24, 52].
It was therefore not surprising to find that children with
ABU express lower levels of the TLR4 than age-matched
controls or children with acute pyelonephritis [52]. However,
the genetic basis for low TLR4 expression is not explained by
structural gene variation, but rather by mutations in the TLR4
promoter that reduce the efficiency of TLR4 expression [23].
We examined TLR4 promoter sequences in two groups of
highly selected UTI-prone patients with either a consistent
pattern of ABU or APN during at least 5 years of follow-up
[23]. The patients were compared to paediatric and adult
controls without UTI. The TLR4 promoter sequences differed
between asymptomatic carriers and controls or patients with
severe disease. The primary ABU patients also had a reduced
Fig. 6 Renal tissue damage in
Irf3−/− mice 7 days after
infection with uropathogenic E.
coli strain 1177. Arrows mark
areas with tissue abscesses.
Virulent strains activate TLR4
signalling and the nuclear
translocation of IRF3. Mice
lacking the Irf3 gene are
therefore highly susceptible,
and surviving mice develop
abscesses and tissue damage
2023
number of genotype patterns and the proportion of specific
promoter genotypes differed compared to the background
population. In contrast, the APN patient group carried the
eight single nucleotide polymorphisms (SNPs) and did not
differ in SNP frequency from the paediatric controls.
A few other studies have focused on ABU, albeit with
different diagnostic criteria. Decreased TLR4 expression was
detected in patients with a history of recurrent UTIs compared
with controls [63]. An increased frequency of three CXCR1
polymorphisms was detected in women with Gram-positive
ABU, [64] but their history of childhood APN was not exam-
ined. A TLR2 polymorphism (2258G > A) was also associated
with ABU [64].
In the murine UTI model, defects in the TLR adaptor
molecules Trif/Tram and MyD88 have also been shown to
protect against symptomatic UTI [24], but to date human
polymorphisms in the corresponding genes have not been
associated with UTI susceptibility.
Genetic variation in acute pyelonephritis
IRF3 polymorphisms P-fimbriated E. coli activate TLR4
signalling. and the IRF3/7 transcription factor enhances
the transcription of innate immune response genes, in-
cluding cytokines and chemokine receptors. Mice lacking
the Irf3 gene develop severe acute pyelonephritis with
urosepsis and renal abscesses (Table 1; Fig. 6) [25] due
to deficient activation of downstream antibacterial effec-
tor functions, such as those dependent on interferons
alpha and beta (INFα, INFβ).
Based on the predictions from the mouse model, we
genotyped pyelonephritis-prone patients for IRF3 promoter
polymorphisms [25]. The results of that study showed that
2024
the IRF3 genotype present in pyelonephritis-prone children
and adults reduced IRF3 promoter activity. IRF3 promoter
sequence variation was detected in two highly UTI-prone
patient populations. One included children in southern Swe-
den who had a consistent UTI pattern over several years:
either severe recurrent APN or ABU, with no prior symp-
tomatic infection. These children were identified on the
basis of a prospective, long-term follow-up of a larger
patient group. The second patient group comprised adults
with a history of childhood febrile UTI who were enrolled in
a prospective study in the 1970s and re-evaluated after about
30 years. Controls were children without UTI-related mor-
bidity and adult blood donors from the same geographic
areas.
DNA sequencing of IRF3 promoters from these UTI
patients revealed variation at the -925 and -776 positions.
SNPs -925 and -776 were linked in the study population
(r2 01.0), but the IRF3 genotype varied with UTI severity
and between cases and controls. In the paediatric group,
most of the APN patients were homozygous for the two
positions, a finding which was confirmed in the adult patients,
with 75% homozygous and 13% heterozygous SNPs com-
pared to 53 and 37%, respectively, in controls. In addition, the
minor allele frequency was decreased in APN compared to
primary ABU and controls.
To examine if IRF3 promoter variation influences tran-
scription efficiency, we cloned promoters from one patient
with APN and one with ABU into a luciferase reporter
vector. Transcriptional activity from the vector with the
APN promoter was about 50% lower than that from the
vector with the ABU promoter, and this difference was
due to the polymorphic sites. The results show that the
IRF3 promoter efficiency is reduced by the SNPs occurring
in about 80% of APN patients, which is consistent with the
finding of human SNPs reducing IRF3 expression and in-
creasing the risk for APN.
CXCR1 polymorphisms In 2000, we showed that mice lack-
ing the IL-8 receptor develop severe acute pyelonephritis
due to a dysfunctional neutrophil response, with urosepsis
and surviving animals showing renal abscess formation and
renal scarring [19].
Based on the predictions from the mouse model, we also
investigated whether the IL-8 receptor (CXCR1 and
CXCR2) is polymorphic in pyelonephritis-prone patients.
Reduced expression of the IL-8 receptor, CXCR1, was
found in children prone to acute pyelonephritis, and the
finding of heterozygous CXCR1 polymorphisms and low
mRNA levels suggested that transcription is impaired in this
patient group [19, 22, 65].
Variants of CXCR1 and related genes have subsequently
been identified in patient groups with different diagnostic
criteria [63, 64, 66, 67]. Reduced CXCR1 expression was
Pediatr Nephrol (2012) 27:2017–2029
confirmed in patients with APN onset before 15 years of
age, and reduced CXCR2 levels were found in girls with
recurrent UTI. IL-8 (CXCL8) SNPs were detected in patients
with confirmed APN without VUR, further supporting a role
of chemokines and their receptors in the antibacterial de-
fense against UTI and the addition of CXCR2 and CXCL8 to
the susceptibility gene repertoire.
Other polymorphisms A CCL5 variant has been shown to
differ between APN-prone children and controls [68]. A
TNF variant (-238G/A) showed increased frequency in
UTI-prone patients with early rheumatoid arthritis [69]. In
Egyptian children with APN, two transforming growth
factor-beta 1 (TGF-β1) variants and two detected vascular
endothelial growth factor (VEGF) promoter variants were
more frequent in patients with scarring than in healthy
controls, but were not linked to VUR [70]. Both TGF-β1
and VEGF promoter variants were associated with renal
scarring in Irish children [71] but not in a group of Asian
patients with renal scarring, indicating variation between
ethnic groups [72]. In addition to promoter polymorphisms,
genetic variants affecting coding regions of lymphotoxin α
[69] and TLR5 1174C > T [73] have been associated with
recurrent UTI. Numerous other SNPs have been examined,
without significant UTI associations.
Receptors, P blood group and UTI susceptibility Uropatho-
genic E. coli colonize mucosal surfaces through adhesion;
consequently, resistance to infection can be modified by the
receptor repertoire of the patients and by soluble anti-
adhesive molecules. Early studies by Stamey et al. [74] led
to the proposal that women with recurrent UTIs have in-
creased vaginal carriage of uropathogenic bacteria. Several
research groups subsequently demonstrated that the uroepi-
thelial cells of these women to have an increased tendency
to bind uropathogenic E. coli, reflecting an increased density
of receptors [60, 75–77].
P-fimbriated E. coli bind to the globoseries of glycoli-
pids, which are antigens in the P blood group system.
Through P blood group determination, it is possible to
predict the mucosal receptor repertoire and, therefore, the
P blood group can be used as a marker in epidemiologic
studies. Individuals with blood group P lack both a
critical enzyme involved in P blood group synthesis
and functional receptors for P-fimbriae, leading to the
prediction that they would be more resistant to P-
fimbriated bacterial infection [34]. Children with blood
group P1 run an increased risk of acute pyelonephritis
(about 11-fold) and have increased carriage of P-fimbriated
E. coli in their intestinal flora, which is a UTI risk
factor [60, 75, 76]. Epithelial receptor expression is also
influenced by the ABO blood group, and individuals express-
ing globo-A are preferentially infected by P-fimbriated E. coli
Pediatr Nephrol (2012) 27:2017–2029
that recognize a combined Gala1–4Galb and blood group
A epitope [77].
Anti-adhesive molecules in urine Urine contains soluble
receptor molecules that inhibit bacterial adhesion. Soluble
receptor oligosaccharides or glycoconjugates bind to fimbri-
ae and prevent them from mediating adhesion. The Tamm–
Horsfall protein, which is a constituent of normal urine,
carries terminal mannose residues that bind type 1-
fimbriated E. coli [78], as well as sialic acid residues that
bind S-fimbriae [79, 80]. P-fimbriae, which show the
strongest disease association, have no known soluble inhib-
itors in urine.
Inheritance of UTI susceptibility
Urinary tract infections have been shown to run in families,
and especially sisters, mothers and grandmothers of the
patient have a history of UTI. The inheritance of APN
susceptibility has been examined by surveying several gen-
erations of families of APN-prone children [65]. An in-
creased frequency of APN was detected in both male and
female family members, and the latter also had lower levels
of CXCR1 expression than controls, indicating that CXCR1
expression influences APN susceptibility. However, the fre-
quency of cystitis was similar in both groups, emphasizing
that APN and cystitis are controlled by different pathoge-
netic mechanisms. Scholes et al. detected that susceptibility
to acute cystitis susceptibility is inherited [81]. Another
study showed that 42% of family members of patients with
a history of lower UTI were UTI prone compared to 11% of
controls [82]. In individuals with a family history of UTI,
there is also an increased influence of behavioral factors
[83].
Specific immunity and resistance to UTI
Acute pyelonephritis gives rise to a specific immune re-
sponse after 3–7 days. The mucosal immune response has
a relatively short memory, however, and most patients there-
fore have low levels of specific antibodies in the urine, even
when they suffer from recurrent infections. In experimental
studies, mice lacking a specific immune system have sur-
prisingly not shown a drastic increase in UTI susceptibility
[26, 84], and patients with different specific immuno-
deficiencies do not primarily develop UTI, suggesting that
the specific immune system is mainly involved once the
innate immune response has failed to clear the infection.
The main evidence suggesting that specific immunity
may protect the urinary tract against infection has been
2025
generated through vaccination studies. Early studies showed
that vaccination with formalin-treated whole bacteria mark-
edly increases specific antibody levels. Subsequent studies
have used purified antigens (LPS, kapsel, fimbriae, outer
membrane proteins) [85–87]. The results clearly show that
hyper-immunization can protect against infection, provided
that the vaccine antigen is expressed by the bacterial strain
used for infection and that infectious challenge is given
while the immune response remains active. While the anti-
genic variation in uropathogenic E. coli is a problem for the
implementation of vaccination in UTI, the development of
novel vaccines gives rise to new optimism. Genetic studies
also suggest that genetically susceptible individuals might
be targeted by vaccination, thus identifying a suitable target
population.
Clinical implications
The efficiency of antibiotics in the treatment of symptomatic
UTI has limited interest in new diagnostic and therapeutic
approaches to UTI. However, with the increasing frequency
of antibiotic resistance among uropathogens, attitudes are
changing. It is fortunate that a large body of molecular
information has been gathered, and the current challenge is
to implement the use of such new tools in clinical practice,
not least when hospital administrative structures and cost
awareness challenge each new diagnostic test and therapeu-
tic expense. In view of the frequency of UTI and the con-
sequences of long-term sequelae, it should be easy to defend
a more individualized diagnostic approach and to explore
how prophylaxis and therapy may be diversified to better fit
the needs of individual patients.
Bacterial virulence The new molecular tools make it possi-
ble to distinguish virulent bacteria from avirulent strains
based on their virulence factors. Many candidate markers
or combinations of markers are potential tools for identify-
ing virulent uropathogenic strains, but to date P-fimbrial
expression shows the strongest association with virulence,
defined as the ability to cause acute pyelonephritis in a child
without abnormalities of the urinary tract or other predis-
posing conditions. P-fimbriae occur in 70–90% of acute
pyelonephritis strains and in up to 100% of adults with
urosepsis. In human inoculation studies, the expression of
P-fimbriae alone has been shown to increase the ability of a
non-virulent ABU strain to establish bacteriuria and to trig-
ger the innate host response that underlies the development
of symptoms [88–90].
P-fimbrial detection in the laboratory is based on agglu-
tination of human P blood group-positive erythrocytes or
receptor-coated particles, and the test is simple to imple-
ment. Uropathogenic E. coli strains may be identified by P-
2026
fimbrial expression. Detecting a P-fimbriated strain in a
child with a typical case of acute pyelonephritis would be
confirmatory, while infection with a P-fimbriae negative
strain might suggest host complications that need to be
investigated further. Early studies showed, for example, that
children who develop renal scars are infected with P-
fimbriae-negative strains more often than children with a
single episode of acute pyelonephritis without scar forma-
tion [91]. As genetic aberrations have now been shown to
cause dysfunctional inflammation in the mouse model, a
knowledge of the virulence profile of the infecting strain
might also help in the clinical evaluation of a child with
atypical symptoms.
Host susceptibility Susceptibility to UTI is usually defined
in childhood, and with long-term follow-up the infection pat-
tern with repeated, febrile infections will reveal who is prone to
developing acute pyelonephritis. Some UTI-prone children
consistently develop ABU with no symptomatic episodes in
between (primary ABU), while others develop ABU subse-
quent to a preceding symptomatic episode (secondary ABU).
There has been a lack of tools to distinguish patients at risk of
recurrent severe infections and future renal scarring from those
who will be protected by long-term ABU and who should be
left untreated. There is also a need for suitable parameters that
limit the use of invasive procedures to the patient group that
will benefit the most from these procedures.
Susceptibility is influenced by many different variables
and, clearly, patients with malformations or mechanic dys-
functions leading to obstructions or VUR should be consid-
ered as a separate group. However, most children with UTI
do not have any underlying mechanic defects. Innate im-
mune response biomarkers provide useful diagnostic tools
to evaluate UTI severity and site of infection. It may be
difficult to distinguish acute pyelonephritis from meningitis
or pneumonia in infants with unclear symptoms, elevated
CRP and bacteriuria, but cytokines may be quantified in the
urine. IL-6 and IL-8 are produced by infected cells in the
urinary tract and elevated levels accompany symptomatic
infections. In ABU, IL-6 is rarely elevated and IL-8 levels
are low. Furthermore, high inflammatory volume from
dimercaptosuccinic acid scans in children with acute pyelo-
nephritis increases the risk of renal scarring [92, 93]. Tools
for more extensive cytokine proteomic profiling in urine are
also becoming available.
We propose that the new genetic tools should be applied
as widely as possible in children with UTI. As in cystic
fibrosis, multiple genetic alterations may be expected to
converge on the susceptible phenotype in APN-prone
patients. While more extensive, prospective clinical studies
are needed to define the sensitivity and specificity of such
tests, the known genetic loci that modify the efficiency of
the innate immune response are strong candidate tools to
Pediatr Nephrol (2012) 27:2017–2029
predict future risk of acute pyelonephritis. Alternately, pro-
tection from symptomatic UTI, resulting from TLR4 poly-
morphisms and low innate immune signalling, might be
helpful to identify ABU patients who may safely be left
untreated from those requiring prophylaxis.
As family studies have supported the premise that UTI
susceptibility may be inherited, a thorough family history is
essential for risk assessment in children with UTI. IRF3
promoter polymorphisms may be used to assess the risk
for recurrent acute pyelonephritis and renal scarring. Con-
versely, TLR4 promoter polymorphisms associated with re-
duced TLR4 expression might be used to identify patients
who preferentially develop asymptomatic bacteriuria.
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