Nucleoside-diphosphate kinase of uropathogenic Escherichia coli inhibits caspase-1-dependent pyroptosis facilitating urinary tract infection.

Uropathogenic Escherichia coli (UPEC) is the most common causative agent of urinary tract infection (UTI). UPEC invades bladder epithelial cells (BECs) via fusiform vesicles, escapes into the cytosol, and establishes biofilm-like intracellular bacterial communities (IBCs). Nucleoside-diphosphate kinase (NDK) is secreted by pathogenic bacteria to enhance virulence. However, whether NDK is involved in UPEC pathogenesis remains unclear. Here, we find that the lack of ndk impairs the colonization of UPEC CFT073 in mouse bladders and kidneys owing to the impaired ability of UPEC to form IBCs. Furthermore, we demonstrate that NDK inhibits caspase-1-dependent pyroptosis by consuming extracellular ATP, preventing superficial BEC exfoliation, and promoting IBC formation. UPEC utilizes the reactive oxygen species (ROS) sensor OxyR to indirectly activate the regulator integration host factor, which then directly activates ndk expression in response to intracellular ROS. Here, we reveal a signaling transduction pathway that UPEC employs to inhibit superficial BEC exfoliation, thus facilitating acute UTI.

Insulin receptor signaling engages bladder urothelial defenses that limit urinary tract infection.

Urinary tract infections (UTIs) commonly afflict people with diabetes. To better understand the mechanisms that predispose diabetics to UTIs, we employ diabetic mouse models and altered insulin signaling to show that insulin receptor (IR) shapes UTI defenses. Our findings are validated in human biosamples. We report that diabetic mice have suppressed IR expression and are more susceptible to UTIs caused by uropathogenic Escherichia coli (UPEC). Systemic IR inhibition increases UPEC susceptibility, while IR activation reduces UTIs. Localized IR deletion in bladder urothelium promotes UTI by increasing barrier permeability and suppressing antimicrobial peptides. Mechanistically, IR deletion reduces nuclear factor κB (NF-κB)-dependent programming that co-regulates urothelial tight junction integrity and antimicrobial peptides. Exfoliated urothelial cells or urine samples from diabetic youths show suppressed expression of IR, barrier genes, and antimicrobial peptides. These observations demonstrate that urothelial insulin signaling has a role in UTI prevention and link IR to urothelial barrier maintenance and antimicrobial peptide expression.

Study on the therapeutic mechanism of HJ granules in a rat model of urinary tract infection caused by Escherichia coli.

ETHNOPHARMACOLOGICAL RELEVANCE: Urinary tract infections (UTIs) are globally prevalent infectious diseases, predominantly caused by uropathogenic Escherichia coli (UPEC). The misuse of antibiotics has led to the emergence of several drug-resistant strains. Traditional Chinese Medicine (TCM) has its own advantages in the treatment of UTIs. HJ granules is a herbal formula used for the treatment of UTIs. However, its mechanism of action is not clear. AIM OF THE STUDY: The aim of this study was to investigate the therapeutic efficacy and mechanism of action of HJ granules in a rat model of UTI caused by Escherichia coli (E coli) CFT073. MATERIALS AND METHODS: SD rats were selected to establish a rat UTI model by injecting UPEC strain CFT073 into the bladder using the transurethral placement method. HJ granules were administered to rats after modelling and the efficacy of HJ granule was investigated by measuring urinary decanalogue, inflammatory factors in bladder tissue and pathological changes in the bladder after 3d of administration. Expression of sonic hedgehog (SHH), NOD-like receptor thermoprotein domain 3 (NLRP3), apoptosis-associated speck-like protein (ASC) and activation of cysteinyl aspartate specific proteinase-1 (caspase-1) were detected by western blotting and immunofluorescence staining in rat bladder tissue. NLRP3, ASC and caspase-1, a cysteine-containing aspartic protein, were expressed and activated. RESULTS: The results showed that infection of rats with UPEC resulted in increased pH and erythrocytes in bladder irrigation fluid; increased expression of IL-1ß, IL-6 and SHH and decreased expression of IL-10 in bladder tissue; and significant upregulation of the expression of both SHH and NLRP3 inflammasom and significant activation of NLRP3 inflammasom. HJ granules significantly increased the concentration of IL-10 in the bladder, inhibited the expression of SHH and NLRP3 inflammasom in bladder tissue, and suppressed the activation of NLRP3 inflammasom, thereby reducing inflammatory lesions in bladder tissue. CONCLUSION: HJ granules may improve bladder injury and treat UTIs by inhibiting the expression and activation of NLRP3 inflammasom.

Xanthogranulomatous Ureteritis: A Diagnostic Challenge in a Patient with Bladder Cancer.

Xanthogranulomatous ureteritis is a very rare process characterized by the presence of foamy histiocytes in a background of chronic active inflammation affecting the ureteral wall. Herein, we describe a case of a 64-year-old man with bladder cancer affecting the left posterolateral wall of the bladder. Radiologically, there was a suspicion of multifocal involvement of the ureteral wall. The patient underwent a radical cystectomy with bilateral pelvic lymphadenectomy and a laparoscopic left nephroureterectomy. Histopathologic examination of the radical cystectomy revealed an invasive high-grade urothelial carcinoma. The wall of the left ureter was replaced by abundant foamy histocytes and a mixed inflammatory infiltrate with lymphocytes and plasma cells consistent with xanthogranulomatous ureteritis. In this report, we highlight the importance of awareness of this benign process when observing a ureteral mass in cancer patients.

D-Mannose reduces cellular senescence and NLRP3/GasderminD/IL-1ß-driven pyroptotic uroepithelial cell shedding in the murine bladder.

Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combating stress, and decreased regenerative capacity. Multiple diseases, including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying the impact of aging on the urinary tract mucosa and the correlation between aging and disease remain poorly understood. Here, we show that, relative to young (8-12 weeks) mice, the urothelium of aged (18-24 months) female mice accumulates large lysosomes with reduced acid phosphatase activity and decreased overall autophagic flux in the aged urothelium, indicative of compromised cellular homeostasis. Aged bladders also exhibit basal accumulation of reactive oxygen species (ROS) and a dampened redox response, implying heightened oxidative stress. Furthermore, we identify a canonical senescence-associated secretory phenotype (SASP) in the aged urothelium, along with continuous NLRP3-inflammasome- and Gasdermin-D-dependent pyroptotic cell death. Consequently, aged mice chronically exfoliate urothelial cells, further exacerbating age-related urothelial dysfunction. Upon infection with uropathogenic E. coli, aged mice harbor increased bacterial reservoirs and are more prone to spontaneous recurrent UTI. Finally, we discover that treatment with D-mannose, a natural bioactive monosaccharide, rescues autophagy flux, reverses the SASP, and mitigates ROS and NLRP3/Gasdermin/interleukin (IL)-1ß-driven pyroptotic epithelial cell shedding in aged mice. Collectively, our results demonstrate that normal aging affects bladder physiology, with aging alone increasing baseline cellular stress and susceptibility to infection, and suggest that mannose supplementation could serve as a senotherapeutic to counter age-associated urothelial dysfunction.

Pathogenesis and prognosis of intrarenal reflux.

Scar development in the children's renal cortex with vesicoureteral reflux (VUR) is one of the most important parameters of prognosis. It can develop regardless of the chosen treatment, even after the regression of VUR. The shape of the renal papillae, the ascending urinary tract infection, the greater than third-degree VUR, and finally the increased intra-calyceal pressure, induce the formation of renal scarring in the renal parenchyma. Renal scarring may complicate VUR independently of the therapeutic strategy (conservative or operative) and its regression. For restitution of this entity, many scientific terms have been used and the most common of them is intrarenal reflux (IRR). The effects of VUR on future renal function result from the limited ability of the affected kidney to grow (failure of renal growth) due to the existence of scars in the renal cortex, the worsening of these scars, or finally the creation of new scars. With the present study, we intend to clarify the etiology and the pathophysiology of IRR and the relation of VUR prognosis to newer biomarkers such as N-acetyl-beta-glycosaminidase, beta-2 microglobulin, Pen- traxin- 3 and Liver-type fatty-acid-binding protein.

Transvaginal ultrasonography for trigonitis diagnosis in women.

OBJECTIVE: Chronic trigonitis (CT) is usually diagnosed through cystoscopy which is invasive and expensive. Thus, an accurate non-invasive diagnostic method is necessary. The objective of this study is to determine the efficacy of transvaginal bladder ultrasound (TBU) for CT diagnosis. METHODS: Between 2012 and 2021, 114 women (17-76 years old) with recurrent urinary tract infection (RUTI) and history of antibiotic resistance were evaluated with TBU by a single ultrasonographer. As a control group, TBU was performed in 25 age-matched women with no previous history of UTI, urological or gynecological conditions. All patients with RUTI had undergone a cystoscopy with biopsy for diagnostic confirmation at the time of trigone cauterization. RESULTS: Thickening of trigone mucosa (>3 mm) was detected in all patients with RUTI and represented the most relevant criteria for trigonitis diagnosis on TBU. Other TBU findings in CT are: irregular and interrupted mucosa lining (96.4%), free debris in the urine (85.9%), increased blood flow at doppler (81.5%), mucosa shedding and tissue flaps. Biopsy showed CT with erosive pattern (58%) or non-keratinizing metaplasia (42%). Diagnostic agreement index between TBU and cystoscopy was 100%. In the control group, normal trigone mucosa is ultrasonographically regular, continuous, with thickness ≤3 mm and there is no debris in the urine. CONCLUSIONS: TBU proved to be an efficient, inexpensive and minimally invasive method to diagnose CT. To our knowledge, this is the first article that reports the use of transvaginal ultrasound as an alternative method for diagnosing trigonitis.

A modified biodegradable mesh ureteral stent for treating ureteral stricture disease.

Ureteral stricture disease (USD) is a common urologic condition. Patients with ureteral stricture disease may suffer from ipsilateral flank pain, nausea, urinary calculi, infection, and impaired renal function. The treatments of USD include surgery, followed by implantation of the ureteral stent to aid the drainage of the urine. The traditional ureteral stent may sometimes cause urological infection, encrustation, and discomfort. To decrease the complication of the ureteral stent, we modified the structure and material based on the traditional ureteral stent. The traditional nondegradable Double-J shape tubular ureteral stent was turned into the biodegradable mesh ureteral stent. The modified mesh ureteral stent and Double-J ureteral stent were inserted into the ureters of the USD animals, respectively. The results of the gross morphology, serology, urinalysis, histology, microstructure, et al. demonstrated that modified mesh ureteral stent has a favorable ability in supporting the ureter and has no effect on cell proliferation, migration, apoptosis, and cell cycle of the human uroepithelial cells. The mesh ureteral stent could relieve ureter obstruction and can be slowly biodegraded after 3-5 months of implantation without the need for a second surgery to remove the stent. Compared to the Double-J ureteral stent, the modified mesh ureteral stent has a lower rate of urinary tract infection and less encrustation. It is expected to be an alternative treatment approach for USD. However, due to the limited number of animals and clinical data, further study focused on the application value in clinical practice are essential. STATEMENT OF SIGNIFICANCE: This study demonstrates: 1. A modified biodegradable mesh ureteral stent; 2. Without the need for a second surgery to remove the stent; 3. A lower rate of urinary tract infection and less encrustation than a double-J ureteral stent; 4. An alternative treatment approach for USD.

The impact of reflux pressure on renal scarring in children with sterile vesicoureteral reflux.

INTRODUCTION: Vesicoureteral reflux (VUR) is a complex disease as patient spectrum is variable. Some cases struggle with recurrent febrile urinary tract infections (UTI) and end-up with renal scars despite intervention. While others suffer no clinical problems and need no treatment. The detrimental effect of VUR on kidneys depends on many factors like grade of reflux, detrusor pressure, and presence of voiding dysfunction. The adverse effects of sterile VUR on kidneys is still under discussion. Thus, we assessed the impact of detrusor pressure at VUR onset on renal scarring in children with sterile reflux. MATERIALS AND METHODS: We retrospectively reviewed the five years follow-up data of 38 children who had unilateral VUR without UTI under treatment. No febrile or afebrile UTIs were detected during the follow-up in any children. All children were assessed with annual video-urodynamics and renal scintigraphy for five consecutive years. The detrusor pressure at VUR onset, grade of VUR, presence of involuntary detrusor contractions, bladder capacity and the presence of renal scaring were recorded. All VURs were recorded during the voiding phase and children with VUR during the filling phase were excluded from the study. RESULTS: In the first line of video-urodynamic studies, the mean detrusor pressure at VUR onset was 24.3 ± 14.8 cm/H2O (median 34.5 cm/H2O, min: 6 - max: 47). There was no relation between boys and girls regarding median detrusor pressure at VUR onset (p = 0.356). Eventually, 22 (57.9%) children developed renal scars and ended up with surgery. There was no relation between scar development and age at first presentation (p = 0.888) The cut-off value for detrusor pressure at VUR onset was noted as 26 cm/H2O (AUC: 0.849 [p < 0.01], Figure). In children who developed renal scars eventually, the median detrusor pressure at VUR onset was significantly higher (p < 0.01). DISCUSSION: The detrimental effect of VUR on kidneys is associated with recurrent infections, bladder dysfunction, and detrusor pressure. Dispute over risk of renal scarring in patients with sterile VUR still continues. CONCLUSION: Children in whom VUR start at higher voiding pressures suffer more renal scars. The threshold of voiding detrusor pressure for risky patients is identified as 26 cm/H2O. It is true that patients suffering recurrent febrile UTIs have higher risk of developing renal scarring. However, the impact of sterile reflux should not be underestimated, since renal scars due to sterile reflux may develop in patients under antibiotic prophylaxis.

Combined Application of Aminoglycosides and Ascorbic Acid in the Elimination of Proteus mirabilis Rods Responsible for Causing Catheter-Associated Urinary Tract Infections (CAUTIs)-A Molecular Approach.

Proteus mirabilis is a common cause of catheter-associated urinary tract infections (CAUTIs). In this study, we verified the effectiveness of amikacin or gentamicin and ascorbic acid (AA) co-therapy in eliminating uropathogenic cells, as well as searched for the molecular basis of AA activity by applying chromatographic and fluorescent techniques. Under simulated physiological conditions, a combined activity of the antibiotic and AA supported the growth (threefold) of the P. mirabilis C12 strain, but reduced catheter colonization (≤30%) in comparison to the drug monotherapy. Slight modifications in the phospholipid and fatty acid profiles, as well as limited (≤62%) 2',7'-dichlorofluorescein fluorescence, corresponding to the hydroxyl radical level, allowed for the exclusion of the hypothesis that the anti-biofilm effect of AA was related to membrane perturbations of the C12 strain. However, the reduced (≤20%) fluorescence intensity of propidium iodide, as a result of a decrease in membrane permeability, may be evidence of P. mirabilis cell defense against AA activity. Quantitative analyses of ascorbic acid over time with a simultaneous measurement of the pH values proved that AA can be an effective urine acidifier, provided that it is devoid of the presence of urease-positive cells. Therefore, it could be useful in a prevention of recurrent CAUTIs, rather than in their treatment.

Preferential catabolism of l- vs d-serine by Proteus mirabilis contributes to pathogenesis and catheter-associated urinary tract infection.

Proteus mirabilis is a common cause of urinary tract infection, especially in catheterized individuals. Amino acids are the predominant nutrient for bacteria during growth in urine, and our prior studies identified several amino acid import and catabolism genes as fitness factors for P. mirabilis catheter-associated urinary tract infection (CAUTI), particularly those for d- and l-serine. In this study, we sought to determine the hierarchy of amino acid utilization by P. mirabilis and to examine the relative importance of d- vs l-serine catabolism for critical steps in CAUTI development and progression. Herein, we show that P. mirabilis preferentially catabolizes l-serine during growth in human urine, followed by d-serine, threonine, tyrosine, glutamine, tryptophan, and phenylalanine. Independently disrupting catabolism of either d- or l-serine has minimal impact on in vitro phenotypes while completely disrupting both pathways decreases motility, biofilm formation, and fitness due to perturbation of membrane potential and cell wall biosynthesis. In a mouse model of CAUTI, loss of either serine catabolism system decreased fitness, but disrupting l-serine catabolism caused a greater fitness defect than disrupting d-serine catabolism. We, therefore, conclude that the hierarchical utilization of amino acids may be a critical component of P. mirabilis colonization and pathogenesis within the urinary tract.

Common anti-haemostatic medications increase the severity of systemic infection by uropathogenic Escherichia coli.

Uropathogenic Escherichia coli (UPEC) causes urinary tract infections that can result in sepsis. The haemostatic system is protective in the pyelonephritis stage of ascending UPEC infection, but the role of the haemostatic system has not been investigated during sepsis. Here we utilize a zebrafish-UPEC systemic infection model to visualize infection-induced coagulation and examine the effects of commonly prescribed anti-haemostatic medications on the infection severity. Treatment of systemically infected zebrafish with warfarin, aspirin, or ticagrelor reduced host survival, while stabilization of clots with aminocaproic acid increased host survival. Anti-haemostatic drug treatment increased UPEC burden. Our findings provide evidence that commonly prescribed anti-haemostatic medications may worsen the outcome of severe UPEC infection.

Human Renal Fibroblasts, but Not Renal Epithelial Cells, Induce IL-1ß Release during a Uropathogenic Escherichia coli Infection In Vitro.

Understanding how uropathogenic Escherichia coli (UPEC) modulates the immune response in the kidney is essential to prevent UPEC from reaching the bloodstream and causing urosepsis. The purpose of this study was to elucidate if renal fibroblasts can release IL-1ß during a UPEC infection and to investigate the mechanism behind the IL-1ß release. We found that the UPEC strain CFT073 induced an increased IL-1ß and LDH release from renal fibroblasts, but not from renal epithelial cells. The UPEC-induced IL-1ß release was found to be NLRP3, caspase-1, caspase-4, ERK 1/2, cathepsin B and serine protease dependent in renal fibroblasts. We also found that the UPEC virulence factor α-hemolysin was necessary for IL-1ß release. Conditioned medium from caspase-1, caspase-4 and NLRP3-deficient renal fibroblasts mediated an increased reactive oxygen species production from neutrophils, but reduced UPEC phagocytosis. Taken together, our study demonstrates that renal fibroblasts, but not renal epithelial cells, release IL-1ß during a UPEC infection. This suggest that renal fibroblasts are vital immunoreactive cells and not only structural cells that produce and regulate the extracellular matrix.

Osteopontin Deficiency Ameliorates Prostatic Fibrosis and Inflammation.

Fibrogenic and inflammatory processes in the prostate are linked to the development of lower urinary tract symptoms (LUTS) in men. Our previous studies identified that osteopontin (OPN), a pro-fibrotic cytokine, is abundant in the prostate of men with LUTS, and its secretion is stimulated by inflammatory cytokines potentially to drive fibrosis. This study investigates whether the lack of OPN ameliorates inflammation and fibrosis in the mouse prostate. We instilled uropathogenic E. coli (UTI89) or saline (control) transurethrally to C57BL/6J (WT) or Spp1tm1Blh/J (OPN-KO) mice and collected the prostates one or 8 weeks later. We found that OPN mRNA and protein expression were significantly induced by E. coli-instillation in the dorsal prostate (DP) after one week in WT mice. Deficiency in OPN expression led to decreased inflammation and fibrosis and the prevention of urinary dysfunction after 8 weeks. RNAseq analysis identified that E. coli-instilled WT mice expressed increased levels of inflammatory and fibrotic marker RNAs compared to OPN-KO mice including Col3a1, Dpt, Lum and Mmp3 which were confirmed by RNAscope. Our results indicate that OPN is induced by inflammation and prolongs the inflammatory state; genetic blockade of OPN accelerates recovery after inflammation, including a resolution of prostate fibrosis.

A previously uncharacterized two-component signaling system in uropathogenic Escherichia coli coordinates protection against host-derived oxidative stress with activation of hemolysin-mediated host cell pyroptosis.

Uropathogenic Escherichia coli (UPEC) deploy an array of virulence factors to successfully establish urinary tract infections. Hemolysin is a pore-forming toxin, and its expression correlates with the severity of UPEC infection. Two-component signaling systems (TCSs) are a major mechanism by which bacteria sense environmental cues and respond by initiating adaptive responses. Here, we began this study by characterizing a novel TCS (C3564/C3565, herein renamed orhK/orhR for oxidative resistance and hemolysis kinase/regulator) that is encoded on a UPEC pathogenicity island, using bioinformatic and biochemical approaches. A prevalence analysis indicates that orhK/orhR is highly associated with the UPEC pathotype, and it rarely occurs in other E. coli pathotypes tested. We then demonstrated that OrhK/OrhR directly activates the expression of a putative methionine sulfoxide reductase system (C3566/C3567) and hemolysin (HlyA) in response to host-derived hydrogen peroxide (H2O2) exposure. OrhK/OrhR increases UPEC resistance to H2O2 in vitro and survival in macrophages in cell culture via C3566/C3567. Additionally, OrhK/OrhR mediates hemolysin-induced renal epithelial cell and macrophage death via a pyroptosis pathway. Reducing intracellular H2O2 production by a chemical inhibitor impaired OrhK/OrhR-mediated activation of c3566-c3567 and hlyA. We also uncovered that UPEC links the two key virulence traits by cotranscribing the c3566-c3567 and hlyCABD operons. Taken together, our data suggest a paradigm in which a signal transduction system coordinates both bacterial pathogen defensive and offensive traits in the presence of host-derived signals; and this exquisite mechanism likely contributes to hemolysin-induced severe pathological outcomes.

Interleukin-6 mediates delirium-like phenotypes in a murine model of urinary tract infection.

BACKGROUND: Urinary tract infection (UTI) is frequently implicated as a precipitant of delirium, which refers to an acute confusional state that is associated with high mortality, increased length of stay, and long-term cognitive decline. The pathogenesis of delirium is thought to involve cytokine-mediated neuronal dysfunction of the frontal cortex and hippocampus. We hypothesized that systemic IL-6 inhibition would mitigate delirium-like phenotypes in a mouse model of UTI. METHODS: C57/BL6 mice were randomized to either: (1) non-UTI control, (2) UTI, and (3) UTI + anti-IL-6 antibody. UTI was induced by transurethral inoculation of 1 × 108 Escherichia coli. Frontal cortex and hippocampus-mediated behaviors were evaluated using functional testing and corresponding structural changes were evaluated via quantification of neuronal cleaved caspase-3 (CC3) by immunohistochemistry and western blot. IL-6 in the brain and plasma were evaluated using immunohistochemistry, ELISA, and RT-PCR. RESULTS: Compared to non-UTI control mice, mice with UTI demonstrated significantly greater impairments in frontal and hippocampus-mediated behaviors, specifically increased thigmotaxis in Open Field (p < 0.05) and reduced spontaneous alternations in Y-maze (p < 0.01), while treatment of UTI mice with systemic anti-IL-6 fully reversed these functional impairments. These behavioral impairments correlated with frontal and hippocampal neuronal CC3 changes, with significantly increased frontal and hippocampal CC3 in UTI mice compared to non-UTI controls (p < 0.0001), and full reversal of UTI-induced CC3 neuronal changes following treatment with systemic anti-IL-6 antibody (p < 0.0001). Plasma IL-6 was significantly elevated in UTI mice compared to non-UTI controls (p < 0.01) and there were positive and significant correlations between plasma IL-6 and frontal CC3 (r2 = 0.5087/p = 0.0028) and frontal IL-6 and CC3 (r2 = 0.2653, p < 0.0001). CONCLUSIONS: These data provide evidence for a role for IL-6 in mediating delirium-like phenotypes in a mouse model of UTI. These findings provide pre-clinical justification for clinical investigations of IL-6 inhibitors to treat UTI-induced delirium.

A mouse model displays host and bacterial strain differences in Aerococcus urinae urinary tract infection.

In recent years, the clinical significance of Aerococcus urinae has been increasingly recognized. A. urinae has been implicated in cases of urinary tract infection (UTI; acute cystitis and pyelonephritis) in both male and female patients, ranging from children to older adults. Aerococcus urinae can also be invasive, causing urosepsis, endocarditis, and musculoskeletal infections. Mechanisms of pathogenesis in A. urinae infections are poorly understood, largely due to the lack of an animal model system. In response to this gap, we developed a model of A. urinae urinary tract infection in mice. We compared A. urinae UTI in female C3H/HeN and C57BL/6 mice and compared four clinical isolates of A. urinae isolated from patients with UTI, urgency urinary incontinence, and overactive bladder. Our data demonstrate that host genetic background modulates A. urinae UTI. Female C57BL/6 female mice rapidly cleared the infection. Female C3H/HeN mice, which have inherent vesicoureteral reflux that flushes urine from the bladder up into the kidneys, were susceptible to prolonged bacteriuria. This result is consistent with the fact that A. urinae infections most frequently occur in patients with underlying urinary tract abnormalities or disorders that make them susceptible to bacterial infection. Unlike uropathogens such as E. coli, which cause infection and inflammation both of the bladder and kidneys in C3H/HeN mice, A. urinae displayed tropism for the kidney, persisting in kidney tissue even after clearance of bacteria from the bladder. Aerococcus urinae strains from different genetic clades displayed varying propensities to cause persistent kidney infection. Aerococcus urinae infected kidneys displayed histological inflammation, neutrophil recruitment and increased pro-inflammatory cytokines. These results set the stage for future research that interrogates host-pathogen interactions between A. urinae and the urinary tract.

A Natural Alternative Treatment for Urinary Tract Infections: Itxasol©, the Importance of the Formulation.

Genito-urinary tract infections have a high incidence in the general population, being more prevalent among women than men. These diseases are usually treated with antibiotics, but very frequently, they are recurrent and lead to the creation of resistance and are associated with increased morbidity and mortality. For this reason, it is necessary to develop new compounds for their treatment. In this work, our objective is to review the characteristics of the compounds of a new formulation called Itxasol© that is prescribed as an adjuvant for the treatment of UTIs and composed of ß-arbutin, umbelliferon and n-acetyl cysteine. This formulation, based on biomimetic principles, makes Itxasol© a broad-spectrum antibiotic with bactericidal, bacteriostatic and antifungal properties that is capable of destroying the biofilm and stopping its formation. It also acts as an anti-inflammatory agent, without the adverse effects associated with the recurrent use of antibiotics that leads to renal nephrotoxicity and other side effects. All these characteristics make Itxasol© an ideal candidate for the treatment of UTIs since it behaves like an antibiotic and with better characteristics than other adjuvants, such as D-mannose and cranberry extracts.