Papers by Catharina Svanborg
Infection and Immunity, 1984
The fitness between bacterial adhesins and target cell receptors, determining bacterial adherence... more The fitness between bacterial adhesins and target cell receptors, determining bacterial adherence to epithelial cells in urinary tract infections, was shown to influence also the interaction with human polymorphonuclear leukocytes (PMNL). Two sets of homogenic strains, constructed to express either, both, or none of the globotetraosylceramide-sensitive (GS) adhesins specific for globoseries glycolipid receptors or the mannose-sensitive (MS) adhesins inhibited by alpha-methyl mannoside were compared regarding charge, hydrophobicity, and binding to PMNL. The mutants of a hydrophilic pyelonephritis strain required MS adhesins for binding to and activation of the PMNL. Removal of the MS adhesins from the mutant carrying both MS and GS adhesins abolished chemiluminescence and binding. A pronounced chemiluminescence reaction was induced by the hydrophobic strain without GS or MS adhesins . Transformants of this strain expressing the MS adhesin bound to and activated the PMNL. Poor binding...
The Journal of Nutrition, 2005
New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET ... more New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET (human ␣-lactalbumin made lethal to tumor cells) offers a new molecular approach to solving this problem, because it induces apoptosis in tumor cells but leaves normal differentiated cells unaffected. After partial unfolding and binding to oleic acid, ␣-lactalbumin forms the HAMLET complex, which enters tumor cells and freezes their metabolic machinery. The cells proceed to fragment their DNA, and they disintegrate with apoptosis-like characteristics. HAMLET kills a wide range of malignant cells in vitro and maintains this activity in vivo in patients with skin papillomas. In addition, HAMLET has striking effects on human glioblastomas in a rat xenograft model. After convection-enhanced delivery, HAMLET diffuses throughout the brain, selectively killing tumor cells and controlling tumor progression without apparent tissue toxicity. HAMLET thus shows great promise as a new therapeutic with the advantage of selectivity for tumor cells and lack of toxicity.
Pathogens, 2016
We have established a novel strategy to reduce the risk for recurrent urinary tract infection (UT... more We have established a novel strategy to reduce the risk for recurrent urinary tract infection (UTI), where rapidly increasing antibiotic resistance poses a major threat. Epidemiologic studies have demonstrated that asymptomatic bacteriuria (ABU) protects the host against symptomatic infections with more virulent strains. To mimic this protective effect, we deliberately establish ABU in UTI-prone patients, who are refractory to conventional therapy. The patients are inoculated with Escherichia coli (E. coli) 83972, now widely used as a prototype ABU strain. Therapeutic efficacy has been demonstrated in a placebo-controlled trial, supporting the feasibility of using E. coli 83972 as a tool to prevent recurrent UTI and, potentially, to outcompete antibiotic-resistant strains from the human urinary tract. In addition, the human inoculation protocol offers unique opportunities to study host-parasite interaction in vivo in the human urinary tract. Here, we review the clinical evidence for protection using this approach as well as some molecular insights into the pathogenesis of UTI that have been gained during these studies.
Pathogens (Basel, Switzerland), Jan 24, 2016
Rapid developments in infection biology create new and exciting options for individualized diagno... more Rapid developments in infection biology create new and exciting options for individualized diagnostics and therapy. Such new practices are needed to improve patient survival and reduce morbidity. Molecular determinants of host resistance to infection are being characterized, making it possible to identify susceptible individuals and to predict their risk for future morbidity. Immunotherapy is emerging as a new strategy to treat infections worldwide and controlled boosting of the host immune defense represents an important therapeutic alternative to antibiotics. In proof of concept studies, we have demonstrated that this approach is feasible. The long-term goal is not just to remove the pathogens but to also develop technologies that restore resistance to infection in disease-prone patients and devise personalized therapeutic interventions. Here, we discuss some approaches to reaching these goals, in patients with urinary tract infection (UTI). We describe critical host signaling pat...
Pathogens, 2016
During asymptomatic bacteriuria (ABU), bacteria colonize the urinary tract for extended periods o... more During asymptomatic bacteriuria (ABU), bacteria colonize the urinary tract for extended periods of time without causing symptoms of urinary tract infection. Previous studies indicate that many Escherichia coli (E. coli) strains that cause ABU have evolved from uropathogenic E. coli (UPEC) by reductive evolution and loss of the ability to express functional virulence factors. For instance, the prototype ABU strain 83972 has a smaller genome than UPEC strains with deletions or point mutations in several virulence genes. To understand the mechanisms of bacterial adaptation and to find out whether the bacteria adapt in a host-specific manner, we compared the complete genome sequences of consecutive reisolates of ABU strain 83972 from different inoculated individuals and compared them with the genome of the parent strain. Reisolates from different hosts exhibited individual patterns of genomic alterations. Non-synonymous SNPs predominantly occurred in coding regions and often affected the amino acid sequence of proteins with global or pleiotropic regulatory function. These gene products are involved in different bacterial stress protection strategies, and metabolic and signaling pathways. Our data indicate that adaptation of E. coli 83972 to prolonged growth in the urinary tract involves responses to specific growth conditions and stresses present in the individual hosts. Accordingly, modulation of gene expression required for survival and growth under stress conditions seems to be most critical for long-term growth of E. coli 83972 in the urinary tract.
Current Opinion in Infectious Diseases, 2015
Purpose of review Urinary tract infections (UTIs) are common, dangerous and interesting. Suscepti... more Purpose of review Urinary tract infections (UTIs) are common, dangerous and interesting. Susceptible individuals experience multiple, often clustered episodes, and in a subset of patients, infections progress to acute pyelonephritis (APN), sometimes accompanied by uro-sepsis. Others develop asymptomatic bacteriuria (ABU). Here, we review the molecular basis for these differences, with the intention to distinguish exaggerated host responses that drive disease from attenuated responses that favour protection and to highlight the genetic basis for these extremes, based on knockout mice and clinical studies. Recent findings The susceptibility to UTI is controlled by specific innate immune signalling and by promoter polymorphisms and transcription factors that modulate the expression of genes controlling these pathways. Gene deletions that disturb innate immune activation either favour asymptomatic bacteriuria or create acute morbidity and disease. Promoter polymorphisms and transcription factor variants affecting those genes are associated with susceptibility in UTI-prone patients. Summary It is time to start using genetics in UTI-prone patients, to improve diagnosis and to assess the risk for chronic sequels such as renal malfunction, hypertension, spontaneous abortions, dialysis and transplantation. Furthermore, the majority of UTI patients do not need follow-up, but for lack of molecular markers, they are unnecessarily investigated.
Advances in Experimental Medicine and Biology
Mucosal surfaces are continuously exposed to a diverse environmental microflora. Yet, infections ... more Mucosal surfaces are continuously exposed to a diverse environmental microflora. Yet, infections are fairly rare and health is maintained. So, how is this achieved? Many and diverse effectors of the host defense have converged at mucosal sites and cooperate to resist the onslaught of pathogens. These are commonly assigned to two categories; the specific or the ‘’innate‘’ defenses. Specific immunity is executed by different lymphocyte populations in response to specific microbial antigens. The term ‘’innate’’ immunity is used to denote the defenses, which lack antigen specificity, but execute their defense functions through effector molecules with highly specialized anti-microbial activity. While many aspects of specific and ‘’innate’’ defense mechanisms have been worked out in vitro , we understand relatively little about their contribution to host resistance in vivo at a given infection site.
PLoS ONE, 2011
The severity of urinary tract infection (UTI) reflects the quality and magnitude of the host resp... more The severity of urinary tract infection (UTI) reflects the quality and magnitude of the host response. While strong local and systemic innate immune activation occurs in patients with acute pyelonephritis, the response to asymptomatic bacteriuria (ABU) is low. The immune response repertoire in ABU has not been characterized, due to the inherent problem to distinguish bacterial differences from host-determined variation. In this study, we investigated the host response to ABU and genetic variants affecting innate immune signaling and UTI susceptibility. Patients were subjected to therapeutic urinary tract inoculation with E. coli 83972 to ensure that they were exposed to the same E. coli strain. The innate immune response repertoire was characterized in urine samples, collected from each patient before and after inoculation with bacteria or PBS, if during the placebo arm of the study. Long-term E. coli 83972 ABU was established in 23 participants, who were followed for up to twelve months and the innate immune response was quantified in 233 urine samples. Neutrophil numbers increased in all but two patients and in an extended urine cytokine/chemokine analysis (31 proteins), the chemoattractants IL-8 and GRO-a, RANTES, Eotaxin-1 and MCP-1, the T cell chemoattractant and antibacterial peptide IP-10, inflammatory regulators IL-1-a and sIL-1RA and the T lymphocyte/dendritic cell product sIL-2Ra were detected and variably increased, compared to sterile samples. IL-6, which is associated with symptomatic UTI, remained low and numerous specific immune mediators were not detected. The patients were also genotyped for UTI-associated IRF3 and TLR4 promoter polymorphisms. Patients with ABU associated TLR4 polymorphisms had low neutrophil numbers, IL-6, IP-10, MCP-1 and sIL-2Ra concentrations. Patients with the ABU-associated IRF3 genotype had lower neutrophils, IL-6 and MCP-1 responses than the remaining group. The results suggest that the host-specific, low immune response to ABU mainly includes innate immune mediators and that host genetics directly influence the magnitude of this response.
Protein Science, 2003
HAMLET (human ␣-lactalbumin made lethal to tumor cells) is a complex of human ␣-lactalbumin and o... more HAMLET (human ␣-lactalbumin made lethal to tumor cells) is a complex of human ␣-lactalbumin and oleic acid (C18:1:9 cis) that kills tumor cells by an apoptosis-like mechanism. Previous studies have shown that a conformational change is required to form HAMLET from ␣-lactalbumin, and that a partially unfolded conformation is maintained in the HAMLET complex. This study examined if unfolding of ␣-lactalbumin is sufficient to induce cell death. We used the bovine ␣-lactalbumin Ca 2+ site mutant D87A, which is unable to bind Ca 2+ , and thus remains partially unfolded regardless of solvent conditions. The D87A mutant protein was found to be inactive in the apoptosis assay, but could readily be converted to a HAMLET-like complex in the presence of oleic acid. BAMLET (bovine ␣-lactalbumin made lethal to tumor cells) and D87A-BAMLET complexes were both able to kill tumor cells. This activity was independent of the Ca 2+ site, as HAMLET maintained a high affinity for Ca 2+ but D87A-BAMLET was active with no Ca 2+ bound. We conclude that partial unfolding of ␣-lactalbumin is necessary but not sufficient to trigger cell death, and that the activity of HAMLET is defined both by the protein and the lipid cofactor. Furthermore, a functional Ca 2+ -binding site is not required for conversion of ␣-lactalbumin to the active complex or to cause cell death. This suggests that the lipid cofactor stabilizes the altered fold without interfering with the Ca 2+ site.
Protein Science, 2005
The stability toward thermal and urea denaturation was measured for HAMLET (human ␣-lactalbumin m... more The stability toward thermal and urea denaturation was measured for HAMLET (human ␣-lactalbumin made lethal to tumor cells) and ␣-lactalbumin, using circular dichroism and fluorescence spectroscopy as well as differential scanning calorimetry. Under all conditions examined, HAMLET appears to have the same or lower stability than ␣-lactalbumin. The largest difference is seen for thermal denaturation of the calcium free (apo) forms, where the temperature at the transition midpoint is 15°C lower for apo HAMLET than for apo ␣-lactalbumin. The difference becomes progressively smaller as the calcium concentration increases. Denaturation of HAMLET was found to be irreversible. Samples of HAMLET that have been renatured after denaturation have lost the specific biological activity toward tumor cells. Three lines of evidence indicate that HAMLET is a kinetic trap: (1) It has lower stability than ␣-lactalbumin, although it is a complex of ␣-lactalbumin and oleic acid; (2) its denaturation is irreversible and HAMLET is lost after denaturation; (3) formation of HAMLET requires a specific conversion protocol.
Protein Science, 2004
A combination of hydrogen/deuterium (H/D) exchange and limited proteolysis experiments coupled to... more A combination of hydrogen/deuterium (H/D) exchange and limited proteolysis experiments coupled to mass spectrometry analysis was used to depict the conformation in solution of HAMLET, the folding variant of human ␣-lactalbumin, complexed to oleic acid, that induces apoptosis in tumor and immature cells. Although near-and far-UV CD and fluorescence spectroscopy were not able to discriminate between HAMLET and apo-␣-lactalbumin, H/D exchange experiments clearly showed that they correspond to two distinct conformational states, with HAMLET incorporating a greater number of deuterium atoms than the apo and holo forms. Complementary proteolysis experiments revealed that HAMLET and apo are both accessible to proteases in the -domain but showed substantial differences in accessibility to proteases at specific sites. The overall results indicated that the conformational changes associated with the release of Ca 2+ are not sufficient to induce the HAMLET conformation. Metal depletion might represent the first event to produce a partial unfolding in the -domain of ␣-lactalbumin, but some more unfolding is needed to generate the active conformation HAMLET, very likely allowing the protein to bind the C18:1 fatty acid moiety. On the basis of these data, a putative binding site of the oleic acid, which stabilizes the HAMLET conformation, is proposed.
Proceedings of the National Academy of Sciences, 2000
In this study α-lactalbumin was converted from the regular, native state to a folding variant wit... more In this study α-lactalbumin was converted from the regular, native state to a folding variant with altered biological function. The folding variant was shown to induce apoptosis in tumor cells and immature cells, but healthy cells were resistant to this effect. Conversion to HAMLET (human α-lactalbumin made lethal to tumor cells) required partial unfolding of the protein and a specific fatty acid, C18:1, as a necessary cofactor. Conversion was achieved with α-lactalbumin derived from human milk whey and with recombinant protein expressed in Escherichia coli . We thus have identified the folding change and the fatty acid as two key elements that define HAMLET, the apoptosis-inducing functional state of α-lactalbumin. Although the environment in the mammary gland favors the native conformation of α-lactalbumin that serves as a specifier in the lactose synthase complex, the conditions under which HAMLET was formed resemble those in the stomach of the nursing child. Low pH is known to r...
PLoS ONE, 2011
Background: Apoptosis is the primary means for eliminating unwanted cells in multicellular organi... more Background: Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. Methodology/Principal Findings: We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity) to execute cell death. Conclusions/Significance: Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells.
Kidney International, 2008
The murine chemokine receptor 2 (mCXCR2) controls resistance to urinary tract infection. We have ... more The murine chemokine receptor 2 (mCXCR2) controls resistance to urinary tract infection. We have previously shown that mCXCR2 knockout mice develop severe acute pyelonephritis and renal tissue damage with sub-epithelial neutrophil entrapment. In this study we examined the relative importance of neutrophil-and epithelial-specific mCXCR2 expression for bacterial clearance in bone marrow chimeric mice infected with uropathogenic Escherichia coli. Mice expressing mCXCR2 on their neutrophils responded rapidly to experimental urinary tract infection, clearing the infection from the kidneys. Mice lacking epithelial mCXCR2, however, showed delayed exit of neutrophils from the tissues. Mice lacking neutrophil mCXCR2 and mice with no mCXCR2 had no neutrophil recruitment and bacterial clearance. Mice expressing mCXCR2 only in their epithelial cells had a transient epithelial chemokine response; however, neutrophil recruitment was inhibited and bacteria grew without constraint. Our study shows that the expression of mCXCR2 on hematopoietic cells was crucial for bacterial clearance, while its expression on non-bone marrow-derived cells influenced the neutrophil response. These results emphasize the importance of mCXCR2 for the innate defense against urinary tract infection.
Kidney International, 2011
The CXCR1 receptor and chemokine CXCL8 (IL-8) support neutrophil-dependent clearance of uropathog... more 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, compared to mCxcr2 -/-and mCxcr2 +/+ mice. Acute sepsis-associated mortality increased drastically in heterozygous compared to wild type mice and bacterial clearance was impaired. The chemokine and neutrophil responses were delayed and there was evidence of neutrophil retention and unresolved kidney inflammation one month after infection, accompanied by epithelial proliferation and sub-epithelial fibrosis. The heterozygous phenotype was thus intermediate, between the mCxcr2 -/-and mCxcr2 +/+ mice, but the specific immune cell infiltrates that accompany chronic infection in mCxcr2 -/-mice were not observed. The results indicate that a heterozygous mCxcr2 defect impairs the innate immune response against acute pyelonephritis, increases the risk for urosepsis and prolongs the infection. The known heterozygous human hCXCR1 polymorphisms might thus predispose patients to acute pyelonephritis and urosepsis.
Kidney International, 2007
The defense against mucosal infections relies on chemokines that recruit inflammatory cells to th... more The defense against mucosal infections relies on chemokines that recruit inflammatory cells to the mucosa. This study examined if the chemokine response to uro-pathogenic Escherichia coli is influenced by fimbrial expression. The CXC (CXCL1, CXCL5, CXCL8, CXCL9, CXCL10) and CC chemokines (CCL2, CCL3, CCL5) were quantified after in vitro infection of uro-epithelial cells with a fimbriated E. coli pyelonephritis isolate, or with P or type 1 fimbriated transformants of an avirulent E. coli K-12 strain. The response profile was shown to vary with the fimbrial type. Type 1 fimbriated E. coli elicited mainly CXCL1 and CXCL8, whereas P fimbriated E. coli stimulated CCL2 and CCL5 and class II were more potent chemokine inducers than class III P fimbriae. Chemokines were also quantified in urine samples from 73 patients with febrile urinary tract infection, and analyzed as a function of disease severity and fimbrial expression by the strain infecting each patient. A complex CXC and CC chemokine response was detected in patient urine, with a significant influence of the fimbrial type. The results show that virulence factors like fimbriae may modify the mucosal chemokine response. This mechanism may allow the host to adjust the inflammatory cell infiltrate to fit the infecting strain.
The Journal of Infectious Diseases, 2000
Interleukin (IL)-8 receptor knockout (KO) mice were shown to have a dysfunctional neutrophil resp... more Interleukin (IL)-8 receptor knockout (KO) mice were shown to have a dysfunctional neutrophil response to urinary tract infection and to develop renal scarring. Intravesical Escherichia coli infection stimulated epithelial chemokine secretion and IL-8 receptor expression in control mice. Neutrophils migrated through the tissues and crossed the epithelial barrier into the urinary tract lumen. In murine IL-8 receptor homologue (mIL-8Rh) KO mice, infection triggered a chemokine response, and neutrophils were recruited but failed to traverse the mucosal barrier and accumulated under the epithelium. After 7 days, control mice were healthy, and infection was cleared, but mIL-8Rh KO mice had swollen kidneys, with neutrophil abscesses and high numbers of bacteria. After 35 days, they developed kidney pathology and renal scarring. The results demonstrate that chemokine receptors drive transepithelial neutrophil migration. In their absence, the neutrophils are trapped, and the tissues are destroyed. This molecular deficiency may determine the progression from acute pyelonephritis to renal scarring. Neutrophils migrate between tissue compartments and exert their effector functions at different sites. They circulate in the blood and interact with the endothelial lining that they cross to reach peripheral tissues. Much attention has focused on the molecular interactions of neutrophils with endothelial cells during the extravasation process [1-3], because this is the key to subsequent pathology and tissue destruction. There is increasing evidence that the fate of neutrophils outside the vascular compartment is governed by specialized molecular interactions distinct from those in the blood vessels [4], but those aspects have received less attention and are not well understood. Mucosal pathogens trigger a rapid neutrophil response [5, 6], and neutrophils are crucial effectors of the host defense at these sites [7, 8]. The mucosal neutrophil response is initiated when bacteria stimulate the epithelial cells to secrete chemokines [6, 9] and to increase their chemokine receptor expression. The neutrophils respond to the so-formed chemotactic gradient, leave the bloodstream, travel through the submucosa, and reach the basal side of the epithelial barrier, which they cross into the lumen [4, 9]. Urinary tract infections (UTIs) are an excellent model to
The Journal of Infectious Diseases, 1999
This study examined the role of neutrophil leukocytes for the antibacterial defense at mucosal in... more This study examined the role of neutrophil leukocytes for the antibacterial defense at mucosal infection sites. Urinary tract infection (UTI) was established by injection into the bladder lumen of Escherichia coli 1177, a fully virulent clinical isolate. Infection of C3H/HeN (lps n , lps n) mice recruited neutrophils into the urinary tract, and bacteria were cleared from kidneys and bladders. The neutrophil response was absent in C3H/HeJ (lps d , lps d) mice, and bacteria persisted in the tissues. Peripheral neutrophil depletion of C3H/HeN mice was subsequently achieved by pretreatment with the granulocyte-specific antibody RB6-8C5. The E. coli-induced neutrophil recruitment was inhibited, as shown by immunohistochemistry and tissue myeloperoxidase quantitation. As a consequence, bacterial clearance from kidneys and bladders was drastically impaired. Antibody treatment of C3H/HeJ mice had only a marginal effect. The results show that neutrophils are essential for bacterial clearance from the urinary tract and that the neutrophil recruitment deficiency in C3H/HeJ mice explains their susceptibility to gram-negative UTI. The resistance of human hosts to microbial attack is astonishing. Health is maintained in the midst of a seemingly overwhelming microflora. This is especially apparent at mucosal surfaces, where most microbes first encounter their hosts [1]. To meet the massive microbial challenge and defend the integrity of underlying tissues, specific immune functions and innate host defenses have converged at these sites [2]. Specific immunity can be particularly effective in preventing infections by pathogens with which the host has had prior experience, but the nonspecific or innate defenses seem to be at least as important in preventing mucosal infections [3-8]. This study examined the antibacterial defense of the urinary tract. Early studies suggested that innate mechanisms might be more important than specific immunity for the early resistance to urinary tract infection (UTI) [3, 5]. Mice with genetic defects in specific immunity (nude, scid, or xid mice) were as resistant to UTI as their immunocompetent littermates, but C3H/HeJ mice were highly susceptible [5-9]. C3H/HeJ mice are designated as lipopolysaccharide (LPS) nonresponders but have a general deficiency in cellular responses involving the Toll-like
The Journal of Infectious Diseases, 2001
Urinary tract infections (UTIs) vary in pathogenesis and severity. After their ascent into the ur... more Urinary tract infections (UTIs) vary in pathogenesis and severity. After their ascent into the urinary tract, bacteria may establish asymptomatic bacteriuria (ABU), cause acute cystitis, or cause acute pyelonephritis. Research during the last few decades has established that the site of infection and the disease severity are influenced by bacterial virulence. In the 1940s, hemolysin was shown to identify Escherichia coli that cause extraintestinal infections [1]. "Uropathogenic" E. coli strains were later shown to belong to a restricted set of serotypes or clones [2], and acute pyelonephritis and ABU strains were shown to differ in surface antigen repertoire [3]. Studies in the 1970s started to involve host cell interactions with attachment to the urinary tract mucosa [4]. We proposed that the disease severity was a direct result of bacterial virulence and that tissue attachment is a first critical step. The special virulence of the uropathogenic clones has subsequently been shown to include numerous virulence factors encoded on the pathogenicity islands (see Middendorf et al., this issue). The variation in urinary tract virulence reflects the ability of bacteria to trigger mucosal and systemic host responses. Through different molecular interactions, bacteria may trigger epithelial cell responses, cause cell detachment, and invade or kill cells by apoptosis (for review see [5]). Inflammation has received special attention because it determines the severity of UTI and the clearance of infection [6] (also see Agace et al. in [5]). We have studied how the inflammatory response is initiated and how it determines the resistance to UTI. Herein we argue that individuals differ in the ability to respond to UTI. We propose that pyelonephritis occurs more readily in "high responders" and that their abnormalities exaggerate the damaging rather than the protective aspects of inflammation. The "low responders," on the other hand, have suppressed inflammatory signals, allowing bacteriuria to establish without harm
Journal of Experimental Medicine, 2000
Neutrophils migrate to infected mucosal sites that they protect against invading pathogens. Their... more Neutrophils migrate to infected mucosal sites that they protect against invading pathogens. Their interaction with the epithelial barrier is controlled by CXC chemokines and by their receptors. This study examined the change in susceptibility to urinary tract infection (UTI) after deletion of the murine interleukin 8 receptor homologue (mIL-8Rh). Experimental UTIs in control mice stimulated an epithelial chemokine response and increased chemokine receptor expression. Neutrophils migrated through the tissues to the epithelial barrier that they crossed into the lumen, and the mice developed pyuria. In mIL-8Rh knockout (KO) mice, the chemokine response was intact, but the epithelial cells failed to express IL-8R, and neutrophils accumulated in the tissues. The KO mice were unable to clear bacteria from kidneys and bladders and developed bacteremia and symptoms of systemic disease, but control mice were fully resistant to infection. The experimental UTI model demonstrated that IL-8R–dep...
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Papers by Catharina Svanborg