Radiation treatment monitoring with DCE-US in CWR22 prostate tumor xenografts.

BACKGROUND: Longitudinal monitoring of potential radiotherapy treatment effects can be determined by dynamic contrast-enhanced ultrasound (DCE-US). PURPOSE: To assess functional parameters by means of DCE-US in a murine subcutaneous model of human prostate cancer, and their relationship to dose deposition and time-frame after treatment. A special focus has been placed to evaluate the vascular heterogeneity of the tumor and on the most suitable data analysis approach that reflects this heterogeneity. MATERIAL AND METHODS: In vivo DCE-US was acquired 24 h and 48 h after radiation treatment with a single dose of 7.5 Gy and 10 Gy, respectively. Tumor vasculature was characterized pixelwise using the Brix pharmacokinetic analysis of the time-intensity curves. RESULTS: Longitudinal changes were detected ( P < 0.001) at 24 h and 48 h after treatment. At 48 h, the eliminating rate constant of the contrast agent from the plasma, kel, was correlated ( P ≤ 0.05) positively with microvessel density (MVD; rτ = 0.7) and negatively with necrosis (rτ = -0.6) for the treated group. Furthermore, Akep, a parameter related to transcapillary transport properties, was also correlated to MVD (rτ = 0.6, P ≤ 0.05). CONCLUSION: DCE-US has been shown to detect vascular changes at a very early stage after radiotherapy, which is a great advantage since DCE-US is non-invasive, available at most hospitals, and is low in cost compared to other techniques used in clinical practice.

Radiation treatment monitoring using multimodal functional imaging: PET/CT ((18)F-Fluoromisonidazole & (18)F-Fluorocholine) and DCE-US.

BACKGROUND: This study aims to assess the effect of radiation treatment on the tumour vasculature and its downstream effects on hypoxia and choline metabolism using a multimodal approach in the murine prostate tumour model CWR22. Functional parameters derived from Positron Emission Tomography (PET)/Computer Tomography (CT) with (18)F-Fluoromisonidazole ((18)F-FMISO) and (18)F-Fluorocholine ((18)F-FCH) as well as Dynamic Contrast-Enhanced Ultrasound (DCE-US) were employed to determine the relationship between metabolic parameters and microvascular parameters that reflect the tumour microenvironment. Immunohistochemical analysis was employed for validation. METHODS: PET/CT and DCE-US were acquired pre- and post-treatment, at day 0 and day 3, respectively. At day 1, radiation treatment was delivered as a single fraction of 10 Gy. Two experimental groups were tested for treatment response with (18)F-FMISO and (18)F-FCH. RESULTS: The maximum Standardized Uptake Values (SUVmax) and the mean SUV (SUVmean) for the (18)F-FMISO group were decreased after treatment, and the SUVmean of the tumour-to-muscle ratio was correlated to microvessel density (MVD) at day 3. The kurtosis of the amplitude of the contrast uptake A was significantly decreased for the control tumours in the (18)F-FCH group. Furthermore, the eliminating rate constant of the contrast agent from the plasma k el derived from DCE-US was negatively correlated to the SUVmean of tumour-to-muscle ratio, necrosis and MVD. CONCLUSIONS: The present study suggests that the multimodal approach using (18)F-FMISO PET/CT and DCE-US seems reliable in the assessment of both microvasculature and necrosis as validated by histology. Thus, it has valuable diagnostic and prognostic potential for early non-invasive evaluation of radiotherapy.

Survival in amoeba--a major selection pressure on the presence of bacterial copper and zinc resistance determinants? Identification of a "copper pathogenicity island".

The presence of metal resistance determinants in bacteria usually is attributed to geological or anthropogenic metal contamination in different environments or associated with the use of antimicrobial metals in human healthcare or in agriculture. While this is certainly true, we hypothesize that protozoan predation and macrophage killing are also responsible for selection of copper/zinc resistance genes in bacteria. In this review, we outline evidence supporting this hypothesis, as well as highlight the correlation between metal resistance and pathogenicity in bacteria. In addition, we introduce and characterize the "copper pathogenicity island" identified in Escherichia coli and Salmonella strains isolated from copper- and zinc-fed Danish pigs.

Inhibition of TIR domain signaling by TcpC: MyD88-dependent and independent effects on Escherichia coli virulence.

Toll-like receptor signaling requires functional Toll/interleukin-1 (IL-1) receptor (TIR) domains to activate innate immunity. By producing TIR homologous proteins, microbes inhibit host response induction and improve their own survival. The TIR homologous protein TcpC was recently identified as a virulence factor in uropathogenic Escherichia coli (E. coli), suppressing innate immunity by binding to MyD88. This study examined how the host MyD88 genotype modifies the in vivo effects of TcpC and whether additional, TIR-domain containing proteins might be targeted by TcpC. In wild type mice (wt), TcpC enhanced bacterial virulence, increased acute mortality, bacterial persistence and tissue damage after infection with E. coli CFT073 (TcpC+), compared to a ΔTcpC deletion mutant. These effects were attenuated in Myd88(-/-) and Tlr4(-/-) mice. Transcriptomic analysis confirmed that TcpC inhibits MYD88 dependent gene expression in CFT073 infected human uroepithelial cells but in addition the inhibitory effect included targets in the TRIF and IL-6/IL-1 signaling pathways, where MYD88 dependent and independent signaling may converge. The effects of TcpC on bacterial persistence were attenuated in Trif (-/-) or Il-1ß (-/-) mice and innate immune responses to ΔTcpC were increased, confirming that Trif and Il-1ß dependent targets might be involved in vivo, in addition to Myd88. Furthermore, soluble TcpC inhibited Myd88 and Trif dependent TLR signaling in murine macrophages. Our results suggest that TcpC may promote UTI-associated pathology broadly, through inhibition of TIR domain signaling and downstream pathways. Dysregulation of the host response by microbial TcpC thus appears to impair the protective effects of innate immunity, while promoting inflammation and tissue damage.

Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection.

The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution of human genetic variation in disease susceptibility. We describe here a new, IRF3-dependent signaling pathway that is critical for distinguishing pathogens from normal flora at the mucosal barrier. Following uropathogenic E. coli infection, Irf3(-/-) mice showed a pathogen-specific increase in acute mortality, bacterial burden, abscess formation and renal damage compared to wild type mice. TLR4 signaling was initiated after ceramide release from glycosphingolipid receptors, through TRAM, CREB, Fos and Jun phosphorylation and p38 MAPK-dependent mechanisms, resulting in nuclear translocation of IRF3 and activation of IRF3/IFNß-dependent antibacterial effector mechanisms. This TLR4/IRF3 pathway of pathogen discrimination was activated by ceramide and by P-fimbriated E. coli, which use ceramide-anchored glycosphingolipid receptors. Relevance of this pathway for human disease was supported by polymorphic IRF3 promoter sequences, differing between children with severe, symptomatic kidney infection and children who were asymptomatic bacterial carriers. IRF3 promoter activity was reduced by the disease-associated genotype, consistent with the pathology in Irf3(-/-) mice. Host susceptibility to common infections like UTI may thus be strongly influenced by single gene modifications affecting the innate immune response.

Acute pyelonephritis and renal scarring are caused by dysfunctional innate immunity in mCxcr2 heterozygous mice.

The CXCR1 receptor and chemokine CXCL8 (IL-8) support neutrophil-dependent clearance of uropathogenic Escherichia coli from the urinary tract. CXCR1 is reduced in children prone to pyelonephritis, and heterozygous hCXCR1 polymorphisms are more common in this patient group than in healthy individuals, strongly suggesting a disease association. Since murine CXCR2 (mCXCR2) is functionally similar to human CXCR1, we determined effects of gene heterozygosity on the susceptibility to urinary tract infection by infecting heterozygous (mCxcr2(+/-)) mice with uropathogenic Escherichia coli. Clearance of infection and tissue damage were assessed as a function of innate immunity in comparison to that in knockout (mCxcr2(-/-)) and wild-type (mCxcr2(+/+)) mice. Acute sepsis-associated mortality was increased and bacterial clearance drastically impaired in heterozygous compared to wild-type mice. Chemokine and neutrophil responses were delayed along with evidence of neutrophil retention and unresolved kidney inflammation 1 month after infection. This was accompanied by epithelial proliferation and subepithelial fibrosis. The heterozygous phenotype was intermediate, between knockout and wild-type mice, but specific immune cell infiltrates that accompany chronic infection in knockout mice were not found. Hence, the known heterozygous CXCR1 polymorphisms may predispose patients to acute pyelonephritis and urosepsis.

Corrigendum: High Presence of Extracellular Hemoglobin in the Periventricular White Matter Following Preterm Intraventricular Hemorrhage.

[This corrects the article DOI: 10.3389/fphys.2016.00330.].

Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs.

Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.

The Dynamics of Platelet Activation during the Progression of Streptococcal Sepsis.

Platelets contribute to inflammation however, the role of platelet activation during the pathophysiological response to invasive bacterial infection and sepsis is not clear. Herein, we have investigated platelet activation in a mouse model of invasive Streptococcus pyogenes infection at 5, 12, and 18 hours post infection and correlated this to parameters of infection. The platelet population in ex-vivo blood samples showed no increased integrin activation or surface presentation of CD62P, however platelet-neutrophil complex formation and plasma levels of CD62P were increased during bacterial dissemination and the progression of sepsis, indicating that platelet activation had occurred in vivo. Platelet-neutrophil complex formation was the most discriminatory marker of platelet activation. Platelet-neutrophil complexes were increased above baseline levels during early sepsis but decreased to significantly lower levels than baseline during late sepsis. The removal of these complexes from the circulation coincided with a significant increase in organ damage and the accumulation of platelets in the liver sinusoids, suggesting that platelet activation in the circulation precedes accumulation of platelets in damaged organs. The results demonstrate that monitoring platelet activation using complementary methods may provide prognostic information during the pathogenesis of invasive S. pyogenes infection.

Bacterial Suppression of RNA Polymerase II-Dependent Host Gene Expression.

Asymptomatic bacteriuria (ABU) is a bacterial carrier state in the urinary tract that resembles commensalism at other mucosal sites. ABU strains often lack the virulence factors that characterize uropathogenic Escherichia coli (E. coli) strains and therefore elicit weak innate immune responses in the urinary tract. In addition, ABU strains are active modifiers of the host environment, which they influence by suppressing RNA polymerase II (Pol II)-dependent host gene expression. In patients inoculated with the ABU strain E. coli 83972, gene expression was markedly reduced after 24 h (>60% of all regulated genes). Specific repressors and activators of Pol II-dependent transcription were modified, and Pol II Serine 2 phosphorylation was significantly inhibited, indicating reduced activity of the polymerase. This active inhibition included disease-associated innate immune response pathways, defined by TLR4, IRF-3 and IRF-7, suggesting that ABU strains persist in human hosts by active suppression of the antibacterial defense. In a search for the mechanism of inhibition, we compared the whole genome sequences of E. coli 83972 and the uropathogenic strain E. coli CFT073. In addition to the known loss of virulence genes, we observed that the ABU strain has acquired several phages and identified the lytic Prophage 3 as a candidate Pol II inhibitor. Intact phage particles were released by ABU during in vitro growth in human urine. To address if Prophage 3 affects Pol II activity, we constructed a Prophage 3 negative deletion mutant in E. coli 83972 and compared the effect on Pol II phosphorylation between the mutant and the E. coli 83972 wild type (WT) strains. No difference was detected, suggesting that the Pol II inhibitor is not encoded by the phage. The review summarizes the evidence that the ABU strain E. coli 83972 modifies host gene expression by inhibition of Pol II phosphorylation, and discusses the ability of ABU strains to actively create an environment that enhances their persistence.

Innate Immune Responses after Airway Epithelial Stimulation with Mycobacterium bovis Bacille-Calmette Guérin.

Mycobacterium bovis bacilli Calmette-Guerin (BCG) is used as a benchmark to compare the immunogenicity of new vaccines against tuberculosis. This live vaccine is administered intradermal, but several new studies show that changing the route to mucosal immunisation represents an improved strategy. We analysed the immunomodulatory functions of BCG on human neutrophils and primary airway epithelial cells (AECs), as the early events of mucosal immune activation are unclear. Neutrophils and the primary epithelial cells were found to express the IL-17A receptor subunit IL-17RA, while the expression of IL-17RE was only observed on epithelial cells. BCG stimulation specifically reduced neutrophil IL-17RA and epithelial IL-17RE expression. BCG induced neutrophil extracellular traps (NETs), but did not have an effect on apoptosis as measured by transcription factor forkhead box O3 (FOXO3). BCG stimulation of AECs induced CXCL8 secretion and neutrophil endothelial passage towards infected epithelia. Infected epithelial cells and neutrophils were not found to be a source of IL-17 cytokines or the interstitial collagenase MMP-1. However, the addition of IFNγ or IL-17A to BCG stimulated primary epithelial cells increased epithelial IL-6 secretion, while the presence of IFNγ reduced neutrophil recruitment. Using our model of mucosal infection we revealed that BCG induces selective mucosal innate immune responses that could lead to induction of vaccine-mediated protection of the lung.

High Presence of Extracellular Hemoglobin in the Periventricular White Matter Following Preterm Intraventricular Hemorrhage.

Severe cerebral intraventricular hemorrhage (IVH) in preterm infants continues to be a major clinical problem, occurring in about 15-20% of very preterm infants. In contrast to other brain lesions the incidence of IVH has not been reduced over the last decade, but actually slightly increased. Currently over 50% of surviving infants develop post-hemorrhagic ventricular dilatation and about 35% develop severe neurological impairment, mainly cerebral palsy and intellectual disability. To date there is no therapy available to prevent infants from developing either hydrocephalus or serious neurological disability. It is known that blood rapidly accumulates within the ventricles following IVH and this leads to disruption of normal anatomy and increased local pressure. However, the molecular mechanisms causing brain injury following IVH are incompletely understood. We propose that extracellular hemoglobin is central in the pathophysiology of periventricular white matter damage following IVH. Using a preterm rabbit pup model of IVH the distribution of extracellular hemoglobin was characterized at 72 h following hemorrhage. Evaluation of histology, histochemistry, hemoglobin immunolabeling and scanning electron microscopy revealed presence of extensive amounts of extracellular hemoglobin, i.e., not retained within erythrocytes, in the periventricular white matter, widely distributed throughout the brain. Furthermore, double immunolabeling together with the migration and differentiation markers polysialic acid neural cell adhesion molecule (PSA-NCAM) demonstrates that a significant proportion of the extracellular hemoglobin is distributed in areas of the periventricular white matter with high extracellular plasticity. In conclusion, these findings support that extracellular hemoglobin may contribute to the pathophysiological processes that cause irreversible damage to the immature brain following IVH.

IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections.

Boosting innate immunity represents an important therapeutic alternative to antibiotics. However, the molecular selectivity of this approach is a major concern because innate immune responses often cause collateral tissue damage. We identify the transcription factor interferon regulatory factor 7 (IRF-7), a heterodimer partner of IRF-3, as a target for non-antibiotics-based therapy of bacterial infections. We found that the efficient and self-limiting innate immune response to bacterial infection relies on a tight balance between IRF-3 and IRF-7. Deletion of Irf3 resulted in overexpression of Irf7 and led to an IRF-7-driven hyperinflammatory phenotype, which was entirely prevented if Irf7 was deleted. We then identified a network of strongly up-regulated, IRF-7-dependent genes in Irf3(-/-) mice with kidney pathology, which was absent in Irf7(-/-) mice. IRF-3 and IRF-7 from infected kidney cell nuclear extracts were shown to bind OAS1, CCL5, and IFNB1 promoter oligonucleotides. These data are consistent in children with low IRF7 expression in the blood: attenuating IRF7 promoter polymorphisms (rs3758650-T and rs10902179-G) negatively associated with recurrent pyelonephritis. Finally, we identified IRF-7 as a target for immunomodulatory therapy. Administering liposomal Irf7 siRNA to Irf3(-/-) mice suppressed mucosal IRF-7 expression, and the mice were protected against infection and renal tissue damage. These findings offer a response to the classical but unresolved question of "good versus bad inflammation" and identify IRF7 as a therapeutic target for protection against bacterial infection.

Mycobacteria bypass mucosal NF-kB signalling to induce an epithelial anti-inflammatory IL-22 and IL-10 response.

The mechanisms by which mycobacteria subvert the inflammatory defence to establish chronic infection remain an unresolved question in the pathogenesis of tuberculosis. Using primary epithelial cells, we have analysed mycobacteria induced epithelial signalling pathways from activation of TLRs to cytokine secretion. Mycobacterium bovis bacilli Calmette-Guerin induced phosphorylation of glycogen synthase kinase (GSK)3 by PI3K-Akt in the signalling pathway downstream of TLR2 and TLR4. Mycobacteria did not suppress NF-κB by activating the peroxisome proliferator-activated receptor γ. Instead the pro-inflammatory NF-κB was bypassed by mycobacteria induced GSK3 inhibition that promoted the anti-inflammatory transcription factor CREB. Mycobacterial infection did not thus induce mucosal pro-inflammatory response as measured by TNFα and IFNγ secretion, but led to an anti-inflammatory IL-10 and IL-22 production. Apart from CREB, MAP3Ks p38 and ERK1/2 activated the transcription factor AP-1 leading to IL-6 production. Interestingly, blocking of TLR4 before infection decreased epithelial IL-6 secretion, but increased the CREB-activated IL-10 production. Our data indicate that mycobacteria suppress epithelial pro-inflammatory production by suppressing NF-κB activation thereby shifting the infection towards an anti-inflammatory state. This balance between the host immune response and the pathogen could determine the outcome of infection.

Epithelial G protein-coupled receptor kinases regulate the initial inflammatory response during mycobacterial infection.

The interaction between mycobacteria and epithelium is unexplored, but may determine the outcome of the infection. We have analyzed the role of two G protein-coupled receptors, CXCR1 and CXCR2 that are important regulators of many pulmonary diseases. We found that mycobacteria significantly increased the expression of both CXCR1 and CXCR2 on alveolar epithelial cells and both receptors were found to be important for neutrophil diapedesis across primary endothelial cells towards infected mucosa. Mycobacteria, lipoarabinomannan or 19-kDa glycolipoprotein up-regulated the inhibitory G protein-coupled receptor kinase (GRK)2, while GRK3 was less affected. Mycobacteria-induced GRK2 up-regulation decreased chemokine transcription and secretion thereby affecting the neutrophil recruitment to infected mucosa. These events were completely abolished by blocking these receptors prior to infection as the blocking increased epithelial immune responses. We have identified novel interactions occurring in the initial phase of mycobacterial infections by which mycobacterial manipulate epithelial inflammatory responses.

Bacterial control of host gene expression through RNA polymerase II.

The normal flora furnishes the host with ecological barriers that prevent pathogen attack while maintaining tissue homeostasis. Urinary tract infections (UTIs) constitute a highly relevant model of microbial adaptation in which some patients infected with Escherichia coli develop acute pyelonephritis, while other patients with bacteriuria exhibit an asymptomatic carrier state similar to bacterial commensalism. It remains unclear if the lack of destructive inflammation merely reflects low virulence or if carrier strains actively inhibit disease-associated responses in the host. Here, we identify a new mechanism of bacterial adaptation through broad suppression of RNA polymerase II­dependent (Pol II­dependent) host gene expression. Over 60% of all genes were suppressed 24 hours after human inoculation with the prototype asymptomatic bacteriuria (ABU) strain E. coli 83972, and inhibition was verified by infection of human cells. Specific repressors and activators of Pol II­dependent transcription were modified, Pol II phosphorylation was inhibited, and pathogen-specific signaling was suppressed in cell lines and inoculated patients. An increased frequency of strains inhibiting Pol II was epidemiologically verified in ABU and fecal strains compared with acute pyelonephritis, and a Pol II antagonist suppressed the disease-associated host response. These results suggest that by manipulating host gene expression, ABU strains promote tissue integrity while inhibiting pathology. Such bacterial modulation of host gene expression may be essential to sustain asymptomatic bacterial carriage by ensuring that potentially destructive immune activation will not occur.

Mycobacterium bovis bacilli Calmette-Guerin regulates leukocyte recruitment by modulating alveolar inflammatory responses.

Leukocyte migration into the epithelial compartment is an important feature in the active phase of mycobacterial infections. In this study, we used the Transwell model to investigate the mechanisms behind mycobacteria-induced leukocyte recruitment and investigated the role of TLR2 and TLR4 in this process. Infection of epithelial cells resulted in significantly increased secretion of the neutrophil chemotactic CXCL8 and IL-6, but no secretion of monocyte chemotactic CCL2 or TNF-α was observed. In contrast to epithelial response, mycobacteria-infected neutrophils and monocytes secreted all these cytokines. Corresponding with epithelial cytokine response, mycobacterial infection of the epithelial cells increased neutrophil diapedesis, but decreased monocyte recruitment. However, monocyte recruitment towards mycobacteria infected epithelial cells significantly increased following addition of neutrophil pre-conditioned medium. Mycobacterial infection also increases alveolar epithelial expression of TLR2, but not TLR4, as analyzed by flow cytometry, Western blotting and visualized by confocal microscopy. Blocking of TLR2 inhibited neutrophil recruitment and cytokine secretion, while blocking of TLR4 had a lesser effect. To summarize, we found that primary alveolar epithelial cells produced a selective TLR2-dependent cytokine secretion upon mycobacterial infection. Furthermore, we found that cooperation between cells of the innate immunity is required in mounting proper antimicrobial defence.

Effect of heparin, fucoidan and other polysaccharides on adhesion of enterohepatic helicobacter species to murine macrophages.

Helicobacter species have been isolated and cultured from both the gastric and enterohepatic niches of the gastrointestinal tract and are associated with a wide spectrum of diseases. Some members of the enterohepatic Helicobacter species (EHS), which include Helicobacter bilis, Helicobacter hepaticus and Helicobacter pullorum, are associated with chronic inflammatory and proliferative bowel inflammation, hepatitis and in experimental murine studies with hepatic cancer. The present study aimed to explore if polysulphated polysaccharides can prevent adhesion of EHS to the murine macrophage cell line J774A.1. A competitive binding assay showed that heparin and heparan sulphate at a concentration of 1.25 mg/ml reduced binding of H. hepaticus and H. pullorum to the host cells, but not H. bilis. Of the tested Helicobacter spp, the highest inhibition by heparin was demonstrated for H. pullorum (P < 0.01), the most hydrophilic strain. Partially or completely de-sulphated heparin derivatives lost the ability to inhibit adherence of EHS, indicating the importance of sulphated groups of heparin. The most efficient inhibitor of EHS binding to macrophages was fucoidan, which reduced bacterial adhesion of the three enterohepatic Helicobacter species to a greater extent than heparin, 60-90% inhibition vs 30-70% inhibition by heparin. Identification of receptors that EHS ligands bind to is important for understanding the development of infection and may provide a rational target to prevent infection and therapy.

Genetics of innate immunity and UTI susceptibility.

A functional and well-balanced immune response is required to resist most infections. Slight dysfunctions in innate immunity can turn the 'friendly' host defense into an unpleasant foe and give rise to disease. Beneficial and destructive forces of innate immunity have been discovered in the urinary tract and mechanisms by which they influence the severity of urinary tract infections (UTIs) have been elucidated. By modifying specific aspects of the innate immune response to UTI, genetic variation either exaggerates the severity of acute pyelonephritis to include urosepsis and renal scarring or protects against symptomatic disease by suppressing innate immune signaling, as in asymptomatic bacteriuria (ABU). Different genes are polymorphic in patients prone to acute pyelonephritis or ABU, respectively, and yet discussions of UTI susceptibility in clinical practice still focus mainly on social and behavioral factors or dysfunctional voiding. Is it not time for UTIs to enter the era of molecular medicine? Defining why certain individuals are protected from UTI while others have severe, recurrent infections has long been difficult, but progress is now being made, encouraging new approaches to risk assessment and therapy in this large and important patient group, as well as revealing promising facets of 'good' versus 'bad' inflammation.