TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections.

The susceptibility to urinary tract infection (UTI) is controlled by the innate immune response and Toll like receptors (TLRs) are the sentinels of this response. If productive, TLR4 signalling may initiate the symptomatic disease process. In the absence of TLR4 signalling the infected host instead develops an asymptomatic carrier state. The activation of mucosal TLR4 is also influenced by the properties of the infecting strain, and pathogens use their virulence factors to trigger 'pathogen-specific' TLR4 responses in the urinary tract but do not respond to the asymptomatic carrier strains in patients with asymptomatic bacteriuria (ABU). The TLR4 dependence has been demonstrated in mice and the relevance of low TLR4 function for protection for human disease was recently confirmed in children with asymptomatic bacteriuria, who expressed less TLR4 than age matched controls. Functional chemokines and functional chemokine receptors are crucial for neutrophil recruitment, and for the neutrophil dependent bacterial clearance. Interleukin (IL)-8 receptor deficient mice develop acute septic infections and chronic tissue damage, due to aberrant neutrophil function. This mechanism is relevant for human UTI as pyelonephritis prone children express low levels of the human CXCL8 (Il-8) receptor, CXC chemokine receptor 1 (CXCR1) and often have heterozygous CXCR1 polymorphisms. This review illustrates how intimately the innate response and the susceptibility to UTI are linked and sophisticated recognition mechanisms that rely on microbial virulence and on host TLR4 and CXCR1 signalling.

Continent urinary tract reconstruction - the Lund experience.

UNLABELLED: The Department of Urology in Lund, Sweden, has a long association with innovations in reconstructive urology. The authors from that department describe their experience over a long period with orthotopic bladder substitution and continent cutaneous urinary diversion. They conclude that continent urinary tract reconstruction is associated with a high incidence of early and late complications. They also found that for storage and emptying, their Lundiana pouch was superior to the Goldwasser neobladder. OBJECTIVE: To assess the early and late complications and functional results in patients undergoing continent reconstruction of the urinary tract, i.e. orthotopic bladder substitution (OBS) or continent cutaneous diversion (CCD). PATIENTS AND METHODS: The medical records of all patients undergoing OBS (Goldwasser technique) or CCD ('Lundiana' technique) for malignant or benign disease during 1987-1999 and followed to December 2001 were reviewed. There were 67 patients with neobladders, 77 with a Lundiana pouch who had undergone radical cystectomy and 22 with a Lundiana pouch operated for benign disorders. RESULTS: Early complications requiring reoperation occurred in 12% of the cystectomy group, with no difference with type of reconstruction, and in 10% with benign diseases. Four patients (3%) undergoing radical cystectomy died from early cardiovascular complications, two after surgery for intra-abdominal complications. Intestinally related complications and wound dehiscence requiring re-operation occurred in nine and six patients, respectively. The incidence of late complications requiring open surgery was 22% and 23% after cystectomy with OBS and CCD, respectively. The value in patients with benign diseases undergoing CCD was also 23%. Stone formation in the pouch was common, occurring in 12% in patients with OBS and in 10% after CCD. The pouch perforated or ruptured in four patients. The incidence of uretero-intestinal stricture using the Le Duc technique was 2.4% and renal function was well preserved. The incidence of revisional surgery of the Lundiana pouch outlet for incontinence was low and all patients but four were continent. The functional outcome in patients with OBS was less good; some needed pouch augmentation or an artificial urinary sphincter. Most patients used incontinence products and many needed clean intermittent self-catheterization. CONCLUSION: Continent urinary tract reconstruction is associated with a high incidence of early and late complications. For storage and emptying, the CCD Lundiana pouch is superior to the OBS of Goldwasser.

[Effect of P fimbriae on pyuria and bacterial colonization of the human urinary tract]. / Der Einfluss von P-Fimbrien auf eine Leukozyturie und den Schwellenwert einer persistierenden Bakteriurie.

This study investigated the role of P fimbriae in colonization of Escherichia coli, host response, and bacterial persistence in humans. Human volunteers were inoculated intravesically with the nonadherent ABU isolate E. coli 83972 and with P fimbriated transformants of the same strain. During the following 24 h all urine samples, and thereafter daily samples, were collected for urine culture, analysis of neutrophil numbers, and cytokine concentrations (IL-6 and IL-8). The P fimbriated transformants showed enhanced bacterial colonization in comparison to E. coli 83972 and lowered the bacterial numbers needed for persistent bacteriuria. The P fimbriated transformants also lowered the bacterial numbers needed for a significant neutrophil and cytokine host response. We conclude that P fimbriae enhance bacterial colonization and trigger the host response in the human urinary tract.

P-fimbriae trigger mucosal responses to Escherichia coli in the human urinary tract.

Uropathogenic Escherichia coli elicit a host response that determines the severity of urinary tract infection (UTI). Specific adherence mechanisms allow the bacteria to initiate this process by targeting epithelial cells in the urinary tract mucosa. Epidemiological studies show a strong association of P-fimbriae with disease severity, suggesting that adherence mediated by these organelles has a direct effect on mucosal inflammation in vivo. The present study examined the ability of P-fimbriae to induce inflammation in the human urinary tract. Patients were subjected to intravesical inoculation with a non-fimbriated E. coli strain or transformants of this strain expressing P-fimbriae. The inflammatory response was analysed as a function of P-fimbrial expression. The P-fimbriated transformants invariably caused higher interleukin (IL)-8, IL-6 and neutrophil responses in the urinary tract than the ABU strain. Furthermore, loss of P-fimbrial expression in vivo was accompanied by a return to background levels of neutrophils, IL-6 and IL-8 in individual patients. The results demonstrate that the pap sequences confer on a non-fimbriated, avirulent strain the ability to induce a host response in the human urinary tract. P-fimbriae thus fulfil the 'molecular Koch-Henle postulates' linking a single virulence factor to host response induction.

The 'innate' host response protects and damages the infected urinary tract.

Symptoms of infection and tissue pathology are caused by the host response; not by the microbe per se. The same response is also critical for the defence and is needed to clear infection. It is therefore essential to understand how the host response is activated and to identify the critical effector mechanisms of the defence. We have studied these issues in the urinary tract infection (UTI) model. The symptoms of UTI and the host defence both rely on the so-called 'innate' immune system, making this one of the best characterized human disease models of 'innate immunity. We discuss the critical molecular events that determine whether the host response will be activated by P-fimbriated uropathogenic Escherichia coli as well as factors determining whether the patient develops acute pyelonephritis or asymptomatic bacteriuria. We will describe the glycoconjugate receptors used by the P-fimbriated bacteria adhering to host tissues, the recruitment of TLR4 co-receptors and the signalling pathways that allow progression to symptomatic disease, and discuss how these mechanisms are altered in asymptomatic carriers, presenting the possible genetic basis for unresponsiveness. We have shown that neutrophils are the critical effectors of the host defence and that neutrophil dysfunctions lead to acute pyelonephritis and renal scarring. Here we discuss the mechanisms of neutrophil-mediated, chemokine receptor (CXCR1)-dependent clearance, and the defect in interleukin-8 receptor homolog knock-out (IL-8Rh KO) mice and describe the data linking low CXCR1 expression to recurrent pyelonephritis in man, as well as the information on the genetic basis for low CXCR1 expression in affected patients. Finally, the mechanisms of renal scarring in IL8Rh KO mice will be discussed in relation to human disease. Our studies hold the promise to provide a molecular and genetic explanation for disease susceptibility in some patients with UTI and to offer more precise tools for the diagnosis and therapy of these infections.

P fimbriae enhance the early establishment of Escherichia coli in the human urinary tract.

This study examined the role of P fimbriae in the establishment of bacteriuria. Patients (n = 17) were subjected to intravesical inoculation with an asymptomatic bacteriuria strain, Escherichia coli 83972, or its P-fimbriated (pap+/prs+) transformants. As shown by groupwise analysis, the pap+/prs+ transformants established bacteriuria more rapidly than E. coli 83972 (P = 0.021) and required a lower number of inoculations to reach 105 cfu ml-1 (P = 0.018). Intraindividual analysis showed that the pap+/prs+ transformants established bacteriuria more rapidly than E. coli 83972 in the patients who subsequently became carriers of both strains. Finally, bacterial establishment was shown to vary with the in vivo expression of P fimbriae. Bacterial counts were higher when P-fimbrial expression was detected than when the pap+/prs+ strain showed a negative phenotype. The results suggested that P fimbriae enhance the establishment of bacteriuria and fulfil the molecular Koch postulates as a colonization factor in the human urinary tract.

Urinary diversion and bladder substitution in patients with bladder cancer.

For the majority of patients with invasive bladder carcinoma, radical cystectomy remains the gold standard of care. As a result the twentieth century has seen the continuous development of methods for reconstructing the urinary tract. Two decades ago the ileal conduit was by far the most commonly used method, whereas today methods geared toward patient continence are first choices in most centers. Some of these methods are unquestionably more complex than the ileal conduit, yet whether they actually yield uniformly improved quality of life is the cause of much debate. Many different variables play a role in determining the best type of reconstruction for an individual bladder cancer patient. This review analyzes the different factors that must be considered to obtain an optimal match between patient and reconstructive method.

Urodynamic factors influence the duration of Escherichia coli bacteriuria in deliberately colonized cases.

PURPOSE: We evaluated the influence of urodynamic factors on the establishment of bacteriuria, after deliberate intravesical inoculation with Escherichia coli. MATERIALS AND METHODS: Nine women and 7 men with recurrent symptomatic urinary tract infections underwent intravesical injection of E. coli 83972. This strain had documented ability to persist in the urinary tract and it lacks expressed virulence factors associated with urinary tract infection. RESULTS: Successful long-term colonization (5 months to 3 years) was achieved in 6 of 12 patients with neurogenic bladder disorder, including normal or high bladder capacity, normal or low detrusor pressure and residual urine. Short-term bacteriuria (13 days) occurred in 1 but long-term bacteriuria was not established in the 4 patients with normal lower urinary tract function. Occasionally urine samples from the colonized patients contained other bacterial strains, which cleared spontaneously except for a Klebsiella strain that became established in 2 and subsequently eliminated E. coli 83972. CONCLUSIONS: E. coli 83972 bacteriuria could only be established in a subset of patients with defective bladder voiding, suggesting that urodynamic defects permit a nonvirulent strain to establish in the urinary tract, but that additional host factors determine if bacteriuria will persist.

Cytokine repertoire of epithelial cells lining the human urinary tract.

PURPOSE: To examine the cytokine profile of epithelial cells lining the human urinary tract with the aim of differentiating between the constitutive and disease-related cytokine production in these tissues. MATERIALS AND METHODS: Sections from the renal pelvis, ureter, bladder or urethra were obtained from 22 patients undergoing urinary tract surgery and were stained with monoclonal antibodies to interleukin(IL)-1beta, IL-4, IL-6, IL-8, interferon gamma (IFNgamma) and transforming growth factor beta (TGFbeta). Sections were classified according to the presence or absence of disease in the tissue. RESULTS: Epithelial cells lining the renal pelvis, ureter, bladder or urethra all stained for IL-8 and TGFbeta (100%) in disease-free tissues and sections with cancer or interstitial cystitis (IC). In contrast, staining for IL-1beta, IL-4, IL-6 and IFNgamma varied with the disease state of the patient. Epithelial IL-1beta staining was absent (0%) in sections from healthy bladder, but positive in tissues with IC or cancer-associated pathology (50 to 100%). IL-6 staining was detected in the epithelial layer of several patients with IC or cancer related pathology, but only in cells with non-epithelial morphology and not in disease-free tissues. IFNgamma and IL-4 staining were only observed in patients with IC and only in cells with non-epithelial morphology. CONCLUSIONS: The results show that epithelial cells from all parts of the urinary tract constitutively produce IL-8 and TGFbeta and suggest that the production of other cytokines varies with the disease of the patient. Constitutive cytokine production provides the basis for a rapid host response, in the defense against mucosal attack by microbes or toxic agents.

Bacterial adherence and mucosal cytokine responses. Receptors and transmembrane signaling.

By attaching to cells or secreted mucosal components, microbes are thought to avoid elimination by the flow of secretions that constantly wash mucosal surfaces. The attached state enhances their ability to trap nutrients and allows the bacteria to multiply more efficiently than do unattached bacterial cells. Attachment is therefore regarded as an end result in itself, and emphasis has been placed on the role of adherence for colonization of mucosal surfaces. Specific adherence was shown to be essential for the tissue tropism that is to guide microbes to their respective sites of colonization/infection. Attachment is not only a mechanism of tissue targeting but also a first step in the pathogenesis of many infections. The attaching bacteria engage in a "cross-talk" with the host cells through the mutual exchange of signals and responses. Enteropathogenic E. coli induce attaching and effacing lesions (Finley et al., this issue). Shigella and Listeria sp. invade the cells and cause actin polymerization (Sansonetti et al., this issue). This review describes the ability of bacteria to trigger mucosal inflammation through activation of cells in the mucosal lining. The results suggest that receptors for bacterial adhesins bind their ligands with a high degree of specificity and that ligand-receptor interactions trigger transmembrane signaling events that cause cell activation. Receptors for microbial ligands thus appear to fulfill also the same criteria as those used to define receptors for other classes of ligands such as hormones, growth factors, and cytokines.

Osteitis pubis after transrectal aspiration biopsy of the prostate.

Two patients developed osteitis pubis after transrectal aspiration biopsy of the prostate. We recommend that prophylactic antibiotics should be given before all such procedures.