Urinary tract infections caused by Pseudomonas aeruginosa: a minireview.
ABSTRACT Urinary tract infections (UTIs) are a serious health problem affecting millions of people each year. Infections of the urinary tract are the second most common type of infection in the body. Catheterization of the urinary tract is the most common factor, which predisposes the host to these infections. Catheter-associated UTI (CAUTI) is responsible for 40% of nosocomial infections, making it the most common cause of nosocomial infection. CAUTI accounts for more than 1 million cases in hospitals and nursing homes annually and often involve uropathogens other than Escherichia coli. While the epidemiology and pathogenic mechanisms of uropathogenic Escherichia coli have been extensively studied, little is known about the pathogenesis of UTIs caused by other organisms like Pseudomonas aeruginosa. Scanty available information regarding pathogenesis of UTIs caused by P. aeruginosa is an important bottleneck in developing effective preventive approaches. The aim of this review is to summarize some of the advances made in the field of P. aeruginosa induced UTIs and draws attention of the workers that more basic research at the level of pathogenesis is needed so that novel strategies can be designed.
- SourceAvailable from: Carlos Molina-Santiago[Show abstract] [Hide abstract]
ABSTRACT: In the human pathogen Pseudomonas aeruginosa, the GltR regulator is required for glucose transport, whereas GtrS is a sensor kinase that plays a key role in mediating bacteria-host interaction and pathogen dissemination in the host. We show that GtrS and GltR form a two-component system that regulates the expression from the promoters Pedd/gap-1, PoprB and Pglk, which control the expression of genes involved in glucose metabolism and transport. In addition, the GtrS/GltR pair regulates the expression of toxA that encodes exotoxin A, the primary virulence factor. Microcalorimetry-based ligand screening of the recombinant GtrS ligand-binding domain revealed specific binding of 2-ketogluconate (2-KG) (KD = 5 μM) and 6-phosphogluconate (KD = 98 μM). These effectors accelerate GtrS autophosphorylation, with concomitant transphosphorylation of GltR leading to a three-fold increase in transcription. Surprisingly, in vivo a similar increase in expression from the above promoters was observed for the mutant deficient in GltR regardless of the presence of effectors. The GltR operator site was found to contain the consensus sequence 5'-tgGTTTTTc-3'. We propose that 2-KG is a key metabolite in the stringent transcriptional control of genes involved in virulence and glucose metabolism. We show that GltR is a transcriptional repressor that is released from DNA upon phosphorylation.Nucleic Acids Research 06/2014; · 8.81 Impact Factor
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ABSTRACT: The nosocomial pathogen Pseudomonas aeruginosa is equipped with a large arsenal of cell- associated and secreted virulence factors, which enhance its invasive potential. The complex relationships among virulence determinants have hitherto not been fully elucidated. In the present study, 175 catheter-related isolates were observed for the presence of selected virulence factors, namely extracellular enzymes and siderophores production, biofilm formation, resistance to antibiotics, and motility. A high percentage of the strains produced most of the tested virulence factors. A positive correlation was identified between the production of several exoproducts, and also between the formation of both types of biofilm. An opposite trend was observed between the two types of biofilm and the production of siderophores. While the relationship between the submerged biofilm production (i.e. the biofilm formed on the solid surface below the water level) and the siderophores secretion was negative, the production of air-liquid interface biofilm (i.e. the biofilm floating on the surface of the cultivation medium) and the siderophores secretion correlated positively. All correlations were statistically significant at the level p=0.05 with the correlation coefficient γ≥0.50. Our results suggest that: (i) the co-production of the lytic enzymes and siderophores can play important role in the pathogenesis of the catheter-related infections and should be taken into account when the virulence potential is assessed; (ii) biofilm-positive strains are capable of forming both submerged and non-attached A-L biofilms; (iii) the different micro-environment in the submerged biofilm and A-L biofilm layers leads to opposite consequences for the production of other virulence factors. This article is protected by copyright. All rights reserved.Foodborne Pathogens and Disease 05/2014; · 2.28 Impact Factor
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ABSTRACT: Background C3 complement plays a pivotal role in the complement cascade, subserves several critical functions in human immune response and enhancing bacterial killing and its levels correlate with infectious diseases. However, the association of C3 with recurrent urinary tract infection (UTI) is still debatable. Aim The aim of this study was to assess the correlation of serum C3 levels and recurrent UTI among young women. Materials and methods Thirty-four recurrent UTI patients whose diagnosed based on Society of Obstetricians and Gynecologists of Canada and European Association of Urology criteria and 34 healthy young women, aged 15–50 years old, were included in this study. Risk factors and clinical manifestations were evaluated and serum C3 levels were measured by ELISA. Correlations of risk factors, clinical manifestation and C3 levels with recurrent UTI were analyzed with chi-square test and Fisher’s exact test or t-test as appropriate with data. Results This study found that some risk factors (age [p = 0.000], sexual intercourse frequency [p = 0.00], marital status [p = 0.000] and intrauterine device contraception [p = 0.000]) and clinical manifestations (fever [p = 0.000], dysuria [p = 0.000], frequent urination [p = 0.000], supra-pubic discomfort [p = 0.000] and flank pain [p = 0.006]) were correlated with recurrent UTI. Although this study found that serum C3 levels were significantly different between recurrent UTI patients and healthy young women group (mean 42.08 μg/ml ± 1.20 vs 42.75 μg/ml ± 0.71, p = 0.008), this difference is not clinically relevant. Conclusion In this study setting, the levels of C3 among young women with recurrent UTI were lower than healthy women but were not significant clinically.Alexandria Journal of Medicine. 05/2014;
Journal of Infection and Public Health (2009) 2, 101—111
Urinary tract infections caused by Pseudomonas
aeruginosa: A minireview
Rahul Mittala,b,∗, Sudhir Aggarwalc, Saroj Sharmab,
Sanjay Chhibberb, Kusum Harjaib
aDivision of Infectious Diseases, Childrens Hospital Los Angeles, Los Angeles, CA, USA
bDepartment of Microbiology, Panjab University, Chandigarh, India
cDepartment of Physiology, University of Tennessee Health Sciences Center, Memphis, TN, USA
Received 1 July 2009; received in revised form 12 August 2009; accepted 13 August 2009
Urinary tract infections;
millions of people each year. Infections of the urinary tract are the second most
common type of infection in the body. Catheterization of the urinary tract is the
most common factor, which predisposes the host to these infections. Catheter-
associated UTI (CAUTI) is responsible for 40% of nosocomial infections, making it
the most common cause of nosocomial infection. CAUTI accounts for more than 1
million cases in hospitals and nursing homes annually and often involve uropathogens
other than Escherichia coli. While the epidemiology and pathogenic mechanisms of
uropathogenic Escherichia coli have been extensively studied, little is known about
the pathogenesis of UTIs caused by other organisms like Pseudomonas aeruginosa.
Scanty available information regarding pathogenesis of UTIs caused by P. aerug-
inosa is an important bottleneck in developing effective preventive approaches.
The aim of this review is to summarize some of the advances made in the field
of P. aeruginosa induced UTIs and draws attention of the workers that more basic
research at the level of pathogenesis is needed so that novel strategies can be
© 2009 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier
Ltd. All rights reserved.
Urinary tract infections (UTIs) are a serious health problem affecting
Virulence factors of uropathogenic P. aeruginosa............................................................
Biofilm formation by P. aeruginosa..........................................................................
Quorum-sensing in P. aeruginosa............................................................................
∗Corresponding author at: Division of Infectious Diseases, MS#51, Childrens Hospital Los Angeles, 4650 Sunset Boulevard,
Los Angeles, CA, 90027, USA. Tel.: +1 323 361 5809.
E-mailaddresses:email@example.com, rahul firstname.lastname@example.org (R. Mittal).
1876-0341/$ — see front matter © 2009 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.
102R. Mittal et al.
Environmental factors and urovirulence of P. aeruginosa....................................................
Host innate immune system and urinary tract infections....................................................
Conflict of interest..........................................................................................
Urinary tract infections (UTIs) are one of the
most common bacterial infections affecting humans
throughout their life span [1,2]. UTIs account for
more than 8 million visits to physician’s offices,
1.5 million emergency room visits, and 300,000
hospital admissions in the United States annually
[3,4]. UTIs are the second most common infec-
tion of any organ system and the most common
urological disease in the United States, with a
total annual cost of more than $3.5 billion .
These infections are more common in females
than in men. Incidence in women in the age of
20—40 years ranges from 25 to 30% whereas in
older women above 60 years of age it ranges
from 4 to 43% [6—8]. UTIs can be classified as
uncomplicated or complicated [9,10]. The rec-
ognized predisposing factors in complicated UTIs
are anatomic defects, vesicouretic reflux (VUR),
obstruction, surgery, metabolic diseases like dia-
betes mellitus and generalized immunosuppression
especially in patients of organ transplant [11—16].
Catheterization of urinary tract is one of the
most common factor which predisposes the host to
complicated UTIs [17—20]. Instillation of catheter
may lead to damage of mucosal layer, which
disrupts the natural barrier and allows bacte-
rial colonization . Organisms can gain entry
via extraluminal route  by moving across
the outer lumen of catheter or by intraluminal
route by directly entering the interior of catheter
The organisms most commonly responsible for
catheter-associated UTIs are Escherichia coli, Pro-
teus mirabilis, Pseudomonas aeruginosa, Klebsiella
pneumoniae and Streptococcus faecalis [6,24—26].
In case of E. coli, the epidemiological, experimen-
tal and clinical studies have established the role of
multiple virulence factors of E. coli like adhesins
operative through type-I fimbriae and P fim-
briae, O serotypes, K1 capsule, serum resistance,
hemolysins, cytotoxic nectrotizing factor (CNF) and
siderophores (enterochelin and aerobactin) in rela-
tion to uncomplicated and complicated UTIs [2,27].
However, there is paucity of literature in relation
to pathogenesis of UTIs caused by P. aeruginosa.
Despite advances in antimicrobial therapy, the mor-
tality and morbidity associated with P. aeruginosa
induced UTIs remain significantly high. This unfa-
vorable outcome is due to our inability to develop
therapeutic strategies to prevent the disease which
in turn is due to incomplete understanding about
the pathogenesis of the disease. The aim of this
review is to highlight some of the most important
advances in understanding the pathogenesis of P.
aeruginosa induced UTIs.
Virulence factors of uropathogenic P.
P. aeruginosa is the third most common pathogen
associated UTIs . Virulence of P. aeruginosa is
multifactorial and has been attributed to cell-
associated factors like alginate, lipopolysaccharide
(LPS), flagellum, pilus and non-pilus adhesins as
well as with exoenzymes or secretory virulence
factors like protease, elastase, phopholipase,
pyocyanin, exotoxin A, exoenzyme S, hemolysins
(rhamnolipids) and siderophores [28—31]. These
factors have been shown to play an important
role in pathogenesis of P. aeruginosa induced
infections like respiratory tract infections, burn
wound infections and keratitis [32—36]. However,
limited reports are available regarding role of these
virulence traits in urinary tract infections. Woods
et al.  showed high production of elastase
and protease in strains isolated from urinary tract
infections in comparison to isolates from other
infections like burn wounds infection, skin wound
infection and acutepneumonia.
analysis of elastase, phospholipase C, toxin A, and
exoenzyme S was assessed in P. aeruginosa strains
isolated from wound infections, respiratory tract
infections and urinary tract infections by Hamood
et al.  It was observed that most of the isolates
produced all the four virulence traits. However
depending on infection site, the isolates produced
varied levels of these virulence determinants.
High levels of elastase and phospholipase C were
Urinary tract infections caused by Pseudomonas aeruginosa: A minireview103
Figure 1 Photograph showing complete encrustation of urinary catheter by biofilms of P. aeruginosa (A) and a higher
magnification showing rod shaped bacteria on the surface of catheter (B).
produced by most isolates obtained from trachea,
urinary tract, and wounds. Significantly higher
levels of toxin A was produced by wound isolates,
while significantly higher level of exoenzyme S
was produced by wound and urinary tract iso-
lates. It was observed that persistent infection
isolates from different sites produce significantly
higher levels of exoenzyme S. These workers
concluded that elastase, phospholipase C, toxin
A, and exoenzyme S are important virulence traits
which help P. aeruginosa to cause a variety of
persistent infections. Ciragil and Soyletir 
investigated relationship between production of
virulence traits and site of infection. These workers
isolated P. aeruginosa strains from cystic fibrosis
patients as well as from lungs, urine and blood
of non-cystic fibrosis patients. It was observed
that urinary isolates produced least amount of
alginate and maximum amount of alkaline protease
as compared to other isolates. Significantly lower
levels of alkaline protease were observed in cystic
fibrosis isolates as compared to other isolates.
No significant difference in elastase levels was
observed among different strains of P. aeruginosa.
However these workers observed no correlation
between elaboration of virulence factors and
site of infection. It was concluded that virulence
factors play an important role in pathogenesis of
infections caused by P. aeruginosa. Visca et al. 
assessed production of virulence determinants in P.
aeruginosa strains isolated from patients suffering
from urinary tract infections. It was observed that
uropathogenic strains of P. aeruginosa produced at
least one type of siderophore i.e. pyochelin and/or
pyoverdin. However not all the uropathogenic
strains produced both siderophores. We reported
that uroisolates of P. aeruginosa produce high
levels of alginate, siderophores, exoenzymes and
hemolysin . However uroisolates possessing
high hemolytic property showed significantly high
renal bacterial counts and marked tissue damage
compared to low producers indicating direct
association between hemolysin production and
renal colonization. It was suggested that besides
considering levels of all extracellular enzymes,
high levels of hemolysin production in vitro could
be used as surrogate information for assessing
pyelonephritic potential of P. aeruginosa. Further
studies employing mutant strains of P. aeruginosa
defective in hemolysin production are required to
elucidate the precise contribution of this virulence
trait to the incidence of UTIs.
Biofilm formation by P. aeruginosa
In addition to elaboration of virulence factors,
P. aeruginosa has a tendency to form biofilms on
the surface of urinary catheters. Growth of P.
aeruginosa begins in the form of microcolonies,
which later coalesce together to form biofilms
(Fig. 1) [41—43]. Alginate, which is an acetylated
polymer of beta-D-mannouronic acid and alpha-L-
guluronic acids, is the most important component
of P. aeruginosa biofilms. However, some other
exopolysaccharides like psl and pel have also
been shown to play an important role in biofilm
forming ability of non-alginate producing strains
of P. aeruginosa [44,45]. Psl is a mannose-rich and
galactose-rich polysaccharide, however the precise
Psl structure has not been elucidated [46—50]. This
is an area requiring future research. As with Psl,
the Pel structure is unknown and further biochem-
ical analyses of Pel polysaccharide is necessary
. Biofilms are resistant to antimicrobial agents
as well as to host defense mechanisms and hence
are difficult to eradicate. Biofilms contribute
towards pathogenicity of P. aeruginosa as these
often lead to persistent and recurrent infections
104R. Mittal et al.
Figure 2 (A) Photograph showing abscess (yellow arrow) and casts (white arrows) along with necrotic changes in renal
tissue of mice infected with biofilm cells of P. aeruginosa. (B) Photograph showing mild inflammation in renal tissue
(white arrow) of mice infected with planktonic cells of P. aeruginosa. (For interpretation of the references to color in
this figure legend, the reader is referred to the web version of the article.)
Once an opportunistic pathogen like P. aerugi-
nosa enters the host, its ability to cause infection
has been correlated with its tendency to form
biofilms [55,56]. P. aeruginosa has an innate
propensity to stick to the surfaces of catheters
and form biofilms leading to higher incidence of
UTIs in patients with long-term indwelling bladder
catheterization [41,47—59]. In addition, previous
microbial urethral colonization could be the cause
of most UTIs where introduction of bacteria into
the bladder takes place subsequently at the time
of catheterization [23,60]. Besides disruption of
the normal valvular function of urethra, catheters
can also traumatize urethral and bladder mucosa,
hence disrupting the normal mucopolysaccharide
coating of the epithelium . This damage of
cellular structure renders it susceptible to attach-
ment as well as entry of bacteria through surface
erosions [62,63]. Therefore, catheter serves as a
direct conduit for pathogens which may be car-
ried from the external meatus to the bladder
when the catheter is introduced . In addi-
tion, internal and external surfaces of catheters
have intrinsic irregularities providing convenient
sites for organism’s implantation as demonstrated
by scanning electron microscopy . Following
initial adherence, bacteria may exude or attract
some products to further solidify attachment .
Costerton et al.  related the pathogenesis
of catheter-associated UTIs to the production of
biofilms by the infecting organisms in which bacte-
rial population adhered to catheter surface through
pili and/or exopolysaccharides. The organisms in
biofilms are able to persist in host’s tissues for
longer durations and are able to cause continuous
damage to the host . In vivo biofilm formation
was reported by Nickel et al.  where coloniz-
ing bacterial population was observed embedded
in glycocalyx on the external and internal sur-
faces of Foley’s catheter removed from patient.
Ganderton et al.  examined 50 Foley blad-
der catheters that had been indwelling for periods
ranging from 3 to 83 days in patients for the
presence of bacterial biofilms. Scanning electron
microscopy revealed biofilm formation on the lumi-
nal surfaces of 44 of these catheters. These workers
observed very thin to very thick biofilms embedded
in a matrix. Stickler et al.  compared nature
of biofilms formed in urease producing and non-
urease producing organisms. It was observed that
urease producing organisms, P. mirabilis, Proteus
nature of biofilms whereas urease-negative bacte-
ria, Morganella morganii, Klebsiella pneumoniae
and P. aeruginosa produced non-crystalline biofilms
on urethral catheter. Similar observation of biofilm
formation in vivo by P. aeruginosa on indwelling
catheter in mice was made by Kurosaka et al.
. In their study, scanning electron microscopy
revealed a thick biofilm formation on the surface
of polyethylene tubing from day 2 onwards which
gradually increased till day 14. Repeatable pattern
of cell death and lysis has been documented to
occur in biofilms of P. aeruginosa during the normal
course of development. During the onset of biofilm
development and biofilm killing thereafter, a bac-
teriophage capable of superinfecting and lysing the
P. aeruginosa parent strain has been detected in
the fluid effluent from the biofilm [72,73]. The bac-
teriophage implicated in biofilm killing was closely
related to the filamentous phage Pf1 which existed
as a prophage within the genome of P. aerugi-
nosa. It has been proposed that prophage-mediated
cell death could be an important mechanism of
differentiation inside microcolonies that facilitate
dispersal of a subpopulation of surviving cells. From
our laboratory we observed that biofilm cells are
able to cause more renal tissue damage compared
Urinary tract infections caused by Pseudomonas aeruginosa: A minireview105
to planktonic counterparts possibly through evasion
of phagocytosis and production of free radicals in
mouse model of ascending UTI (Fig. 2) . Hence
formation of biofilms is the most important virulent
trait of P. aeruginosa which enables this pathogen
to cause recurrent and chronic UTIs by evading host
immune defense mechanisms.
Quorum-sensing in P. aeruginosa
A variety of gram-negative and gram-positive bac-
teria have been reported to monitor their cell
density as well as expression of virulence fac-
tors through chemical signals. These signals known
as quorum-sensing signals are mainly operative
tones (AHLs). In P. aeruginosa two types of
quorum-sensing systems, las  and rhl 
have been reported which consist of two signal-
generating synthetases (LasI RhlI) and two cognate
transcriptional regulators (LasR RhlR). The major
products of LasI and RhlI are N-(3-oxododecanoyl)-
homoserine lactone (OdDHL or 3OC12-HSL) 
and N-butanoylhomoserine lactone (BHL or C4-HSL)
[78,79], respectively. The lasIR encoded quorum-
sensing system has been shown to modulate
expression of lasI itself , lasB (elastase) [81,82],
alkaline protease , secretion pathway  and
rhlR [85,86]. The rhlIR-encoded quorum sensor
modulates expression of rhlI itself , rhlAB
(rhamnolipid biosynthesis) [76,82], lasB [78,82,87]
and rpoS . Both these quorum-sensing systems
are involved in the differentiation of planktonic
cells to biofilm mode . Role of these quorum-
sensing signals in virulence and pathogenicity of
P. aeruginosa has been demonstrated in models of
respiratory tract infections, burn wound infections
and keratitis [89—94]. However, very limited stud-
ies highlighting the role of these signal molecules
in the pathogenesis of urinary tract infections are
available. Stickler and co-workers  reported
production of AHLs by P. aeruginosa isolated from
urethral catheters using cross-feeding assay. These
workers demonstrated production of AHL molecules
in biofilms in vitro as well as in vivo in the patient’s
bladder. Relatively recently from our laboratory, we
reported that quorum-sensing signals play a crucial
role in ability of P. aeruginosa to cause urinary tract
infection . Single mutant harboring mutated las
I gene and double mutant harboring mutated las
I and rhl R as well as quorum deficient clinical
strain of P. aeruginosa were cleared from the renal
tissues much earlier than parent strain possessing
functional las and rhl quorum-sensing systems high-
lighting central role of quorum-sensing signals in
virulence of P. aeruginosa. Recently some new types
of quorum-sensing systems like PQS and have been
identified in P. aeruginosa however their role in UTIs
has yet to be elucidated [96—98].
Environmental factors and urovirulence
of P. aeruginosa
P. aeruginosa has been reported to continuously
stimuli. While establishing in the urinary tract,
presence of urine, which is a complex medium,
exposes invading organism to conditions like varied
osmolarity, pH and Tamm—Horsfall protein (THP)
as well as variability of ions such as iron [99—101].
Urine is subject to change in pH and osmolarity
depending on host’s diet and clinical situation.
Environmental conditions prevalent in the host
mileu may bring about certain changes in organism
like change in outer membrane protein (Omp)
profile, porin size [102,103] and adhesive ability
operative through lectins [99,102,104] which may
play an important role in deciding the ultimate
outcome of an infection.
Iron-limiting conditions have been reported to be
prevalent in the milieu of urinary tract ,
therefore the ability of uropathogens to sequester
iron from the host becomes a significant factor
in determining their growth, metabolic process
and pathogenicity . P. aeruginosa has been
reported to produce two siderophores, pyochelin
and pyoverdin, which help this pathogen to obtain
iron from host’s iron binding proteins like lacto-
ferrin and transferrin. In relation to P. aeruginosa
some in vitro, studies are available where iron
has been shown to regulate production of toxin
A , alkaline protease , elastase [99,107]
and siderophores , the recognized virulence
factors of this opportunistic organism. Iron concen-
tration of the culture medium employed for growth
of P. aeruginosa was also shown to have the poten-
tial to influence pathogenicity of this organism
in corneal  as well as in the acute respira-
tory tract infection model . Recent studies
from our laboratory demonstrated that P. aerug-
inosa grown in iron deplete medium were more
virulent as compared to iron replete grown bacteria
as indicated by higher production of virulence fac-
tors and lodgement of bacteria in the urinary tract
of experimental animals . Hence, existing
literature indicate that levels of iron dictate vir-
106R. Mittal et al.
ulence of P. aeruginosa and are thus critical for its
pathogenicity. Extrapolation of available informa-
tion may help in developing alternative preventive
approach against UTIs based on iron supplementa-
tion with far reaching consequences.
Osmolarity is another important factor which has
been reported to affect growth and virulence of
P. aeruginosa. In order to establish and cause
UTI, P. aeruginosa has to adapt itself to varia-
tions in osmolarity of urine. We observed that
osmolarity has profound influence on uroviru-
lence of P. aeruginosa . There was significant
increase in production of virulence factors with
increase in osmolarity from 200 to 300mOsmol/l.
However further increase in osmolarity led to sig-
nificant decrease in production of virulence factors.
In addition, organisms grown in medium having
osmolarity 300mOsmol/l were resistant to phago-
cytosis and were more virulent in mouse model of
ascending UTI as indicated by significantly higher
neutrophil recruitment, bacterial load, malondi-
aldehyde (MDA) production, a marker of tissue
damage, and renal as well as bladder pathology.
Culham et al.  highlighted that in addition to
directly influencing bacterial growth in the urinary
tract, osmoregulatory mechanisms may indirectly
influence urinary tract infection by affecting the
expression of virulence determinants. In case of
P. aeruginosa, the sigma factor, Rpo S, has been
shown to play an important role during exposure
of this organism to various environmental stresses
including osmotic stress. Suh et al.  also sug-
gested importance of Rpo S in the pathogenesis of
P. aeruginosa induced respiratory infections. There
is strong possibility that similar mechanism may be
operative in the urinary tract affecting the evolu-
tion of infection caused by P. aeruginosa although
this needs further confirmation.
In the urinary tract, complex urine provides a
medium which has copious amounts of mucus. The
urinary mucus predominantly has Tamm—Horsfall
protein (THP) which is a polymeric glycoprotein,
produced in thick ascending limb of loop of Henle
in renal tissue . Majority of THP is in the form
of secreted protein in urine but it also exists in
membrane bound form especially at the renal dis-
tal nephron cell surface . Concentration of
THP has been reported to be crucial in deciding
the ultimate role played by this protein . We
observed that with increase in concentration of THP
from 10 to 50?g/ml, there was gradual rise in elab-
oration of all the virulence factors as compared
to control (i.e. in absence of THP). However with
further increase in concentration of THP from 50
to 70?g/ml there was significant fall in produc-
tion of all the virulence traits by biofilm cells of P.
aeruginosa . Decreased uptake and intracellu-
lar killing of THP (50?g/ml) coated planktonic and
biofilm cells of P. aeruginosa by murine peritoneal
macrophages were also observed. In addition, it
was observed that THP coated P. aeruginosa cells
were more virulent in vivo in UTI model, show-
ing higher level of destruction in kidney as well
as in bladder tissue in comparison to uncoated
organisms . These results therefore bring out
that THP coating provide better opportunity to this
pathogen for survival in vivo by evading phagocyto-
sis. Hawthorn et al.  while comparing adhesion
of three uropathogens to THP coated renal tubular
cells in vitro, also stressed that THP may not help
to remove all uropathogens from urinary tract. It
may help in renal colonization of uropathogens like
P. aeruginosa. In the milieu of the kidney where THP
is available in abundance these observations have
immense relevance. Once P. aeruginosa reaches
renal parenchyma, this ability may help this organ-
ism to colonize, get established and persist. Further
in vivo studies using THP knock-out mice are war-
ranted which can shed more light on the precise
role of THP in P. aeruginosa induced UTIs.
Host innate immune system and urinary
Besides environmental factors, the host also plays
an important role in the establishment of an infec-
tious process. Microbial virulence is dependent on
host factors, as exemplified by the pathogenic-
ity of avirulent microbes in immunocompromised
hosts and the lack of pathogenicity of virulent
pathogens in immune hosts. In this regard the
innate immunity provides a first line of defense
in which macrophages and neutrophils play an
important role. Macrophages, coming mostly from
circulation, form one of the initial lines of defense
in the urinary tract and offer resistance against
infection. These macrophages interact with invad-
ing pathogen leading to elaboration of biochemical
substances referred to as macrophage secretory
products (MSPs). MSPs have been recognized to
contain peptide hormones, complement compo-
nents, enzymes, bioactive oligopeptides and lipids,
reactive oxygen and nitrogen species as well as
cytokines . P. aeruginosa has been reported
Urinary tract infections caused by Pseudomonas aeruginosa: A minireview107
to exploit these MSPs for its own growth and
enhancing production of virulence traits leading to
enhanced virulence in mouse model of ascending
UTI (unpublished data) . Utilization of MSPs by
P. aeruginosa can have far reaching consequences
including chronicity and recurrence of infections
caused by this pathogen. Since MSPs contain a
diverse array of biomolecules which can act in a
complex manner among themselves, further stud-
ies are warranted which can throw more light on
the precise role of MSPs in UTIs.
In addition to macrophages, neutrophils also
provide defense against UTIs operative through
phagocytosis as well as elaboration of cytokines.
On one hand, these cells are essential for clear-
ance of bacteria from urinary tract, on the other
hand neutrophils have been implicated in tissue
damage leading to renal scarring . In case neu-
trophils are trapped and tissue is destroyed, the
kidney pathology has been reported to be progress-
ing to the stage of chronicity and renal scarring.
These cells are recruited to the site of infection
in response to chemokine secretion by bladder and
renal epithelial cells like IL-8. In vitro production
of IL-8 has been studied in cultured epithelial cells
from various sources , where it has been shown
to affect neutrophil chemotaxis, degranulation and
transendothelial migration. High levels of IL-8 have
been demonstrated in urine of patients suffer-
ing from UTIs. Macrophage inflammatory protein-2
(MIP-2) is one of the human IL-8 homologues in the
mouse. Studies from our laboratory demonstrated
that although biofilm cells of P. aeruginosa induce
higher levels of MIP-2 compared to planktonic coun-
terparts leading to more recruitment of neutrophils
but are resistant to killing by neutrophils possibly by
interfering with oxidative burst capacity in mouse
ance of the organism is not based on the collection
of neutrophils but the efficacy of the neutrophils to
kill, especially biofilm forms of P. aeruginosa.
UTIs activate both mucosal and systemic inflam-
matory responses in which cytokines play a pivotal
role [123,124]. Cytokines, both proinflammatory
and anti-inflammatory, have been reported to be
produced largely by macrophages. In addition, wide
variety of cells including lymphocytes, endothe-
lial cells, pulmonary epithelial cells and urinary
tract epithelial cells produce these cytokines in
response to bacteria  or their products like
lipopolysaccharide (LPS) and fimbriae [126—128].
Cytokines like TNF-?, MIP-2, IL-6 and IL-1? have
been reported to be produced in urinary tract fol-
lowing infection with uropathogenic E. coli which
blood to the site of infection [129,130]. Increased
levels of these cytokines and their receptors have
been observed in urine and serum samples of
patients having acute pyelonephritis . How-
ever there is paucity of literature in relation to role
of these cytokines in UTIs caused by P. aeruginosa.
Since cytokines play an important role in recruit-
ing immune cells to the site of infection, further
studies in relation to UTIs are warranted, and will
be of special relevance for clinicians for treating
catheter- and hospital-acquired infections.
Despite advances in antimicrobial therapy the mor-
tality and morbidity associated with P. aeruginosa
induced UTIs still remains high. This unfavorable
outcome is due to our incomplete understanding
about the pathogenesis of the disease. Very limited
studies are available in relation to the pathogenesis
of P. aeruginosa induced UTI. This review draws
attention of the researchers that there is need
to understand pathogenetic mechanisms of UTIs
caused by P. aeruginosa in order to design effective
treatment strategies. Acylhomoserine lactones
(AHLs) can be speculated to serve as potential
target molecules for inhibition of biofilm forma-
tion. In addition, role of bacterial and host factors
during evolution of urinary tract infection caused
by P. aeruginosa needs to be looked into since
such infections, which may lead to persistence and
chronicity, posing a threat for a treating clinician.
Recognizing how P. aeruginosa overrun crucial host-
cell pathways by using a myriad of mechanisms
may help in understanding pathogenesis of UTIs
caused by this pathogen. This knowledge needs
to be advanced to the point at which it can be
translated into a true understanding of the disease.
This remains the crucial challenge to all who are
involved in this field. All this information may
help in developing effective preventive strategies
against biofilms of P. aeruginosa formed on urethral
catheters which are a major cause of recurrence,
persistence and chronicity.
Conflict of interest
Funding: This work was supported by a grant
from Indian Council of Medical Research (ICMR),
New Delhi, India.
Competing interests: None declared.
approved by the institutional ethical committee for
108R. Mittal et al.
We are thankful to Jeenu for the critical read-
ing of the manuscript. This work was supported
by a research grant from Indian Council of Medical
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