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.

ERK (extracellular-signal-regulated kinase) activation leads to disruption of tight junctions in some epithelial monolayers, whereas it prevents disruption of tight junctions in other epithelia. The factors responsible for such contrasting influences of ERK on tight junction integrity are unknown. The present study investigated the effect of the state of cell differentiation on ERK-mediated regulation of tight junctions in Caco-2 cell monolayers. EGF (epidermal growth factor) potentiated H2O2-induced tight junction disruption in under-differentiated cell monolayers, which was attenuated by the MEK [MAPK (mitogen-activated protein kinase)/ERK kinase] inhibitor U0126. In contrast, EGF prevented H2O2-induced disruption of tight junctions in differentiated cell monolayers, which was also attenuated by U0126. Knockdown of ERK1/2 enhanced tight junction integrity and accelerated assembly of tight junctions in under-differentiated cell monolayers, whereas it had the opposite effect in differentiated cell monolayers. Regulated expression of wild-type and constitutively active MEK1 disrupted tight junctions, and the expression of dominant-negative MEK1 enhanced tight junction integrity in under-differentiated cells, whereas contrasting responses were recorded in differentiated cells. EGF prevented both H2O2-induced association of PP2A (protein phosphatase 2A), and loss of association of PKCζ (protein kinase Cζ), with occludin by an ERK-dependent mechanism in differentiated cell monolayers, but not in under-differentiated cell monolayers. Active ERK was distributed in the intracellular compartment in under-differentiated cell monolayers, whereas it was localized mainly in the perijunctional region in differentiated cell monolayers. Thus ERK may exhibit its contrasting influences on tight junction integrity in under-differentiated and differentiated epithelial cells by virtue of differences in its subcellular distribution and ability to regulate the association of PKCζ and PP2A with tight junction proteins.

The role of mitogen-activated protein kinases (MAPK) in the mechanism of EGF-mediated prevention of acetaldehyde-induced tight junction disruption was evaluated in Caco-2 cell monolayers. Pretreatment of cell monolayers with EGF attenuated acetaldehyde-induced decrease in resistance and increase in inulin permeability and redistribution of occludin, zona occludens-1 (ZO-1), E-cadherin, and β-catenin from the intercellular junctions. EGF rapidly increased the levels of phospho-ERK1/2, phospho-p38 MAPK, and phospho-JNK1. Pretreatment of cell monolayers with U-0126 (inhibitor of ERK activation), but not SB-202190 and SP-600125 (p38 MAPK and JNK inhibitors), significantly attenuated EGF-mediated prevention of acetaldehyde-induced changes in resistance, inulin permeability, and redistribution of occludin and ZO-1. U-0126, but not SB-202190 and SP-600125, also attenuated EGF-mediated prevention of acetaldehyde effect on the midregion F-actin ring. However, EGF-mediated preservation of junctional distribution of E-cadherin and β-catenin was unaffected by all three inhibitors. Expression of wild-type or constitutively active MEK1 attenuated acetaldehyde-induced redistribution of occludin and ZO-1, whereas dominant-negative MEK1 prevented EGF-mediated preservation of occludin and ZO-1 in acetaldehyde-treated cells. MEK1 expression did not alter E-cadherin distribution in acetaldehyde-treated cells in the presence or absence of EGF. Furthermore, EGF attenuated acetaldehyde-induced tyrosine-phosphorylation of occludin, ZO-1, claudin-3, and E-cadherin. U-0126, but not SB-202190 and SP-600125, prevented EGF effect on tyrosine-phosphorylation of occludin and ZO-1, but not claudin-3, E-cadherin, or β-catenin. These results indicate that EGF-mediated protection of tight junctions from acetaldehyde requires the activity of ERK1/2, but not p38 MAPK or JNK1/2, and that EGF-mediated protection of adherens junctions is independent of MAPK activities.

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Pseudomonas aeruginosa is one of the leading causes of catheter-associated urinary tract infections (UTIs), associated with high mortality and morbidity. In this study, 50 P. aeruginosa isolates from urine of patients with UTIs were serotyped according to the international antigenic typing system. The majority of the isolates (34%) belonged to serogroup O11, whereas 22%, 10%, 8%, 8%, 6%, 6%, 4% and 2% strains belonged to serogroups OII, O6, O1, O8, O7/8, O3, O4 and O15, respectively. Uroisolates belonging to serogroup O11 were strong biofilm producers, whereas serogroup O6 were weak biofilm producers. O11 serogroup uroisolates also showed increased adhesion to uroepithelium and elaborated higher levels of all the virulence factors. A strong correlation between serotype, in vitro biofilm formation and elaboration of virulence factors was observed. The data suggest that differences in virulence potential according to serotype should be taken into account to design effective preventive strategies against P. aeruginosa-induced UTIs.