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| 2. |
- Ragnarsdottir, Bryndis, et al.
(författare)
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TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections.
- 2008
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38 Suppl 2, s. 12-20
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Forskningsöversikt (refereegranskat)abstract
- 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.
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| 3. |
- Wullt, Björn
(författare)
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The role of P fimbriae for Escherichia coli establishment and mucosal inflammation in the human urinary tract
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bacterial adhesion to the bladder mucosa is a critical step for the establishment of Escherichia coli bacteriuria. The P-fimbriae, encoded by the pap gene cluster, are considered as virulence factors but the mechanisms have been debated. This study defined the roles for P fimbriation during the early colonization of the human urinary tract. Patients with recurrent UTI were first subjected to deliberate colonization with the non-fimbriated ABU strain E. coli 83972. Bacteriuria was established long term (1-4 years) in patients with dysfunctional bladders, but not in the patients with normal bladder function. Super-infections were transient and asymptomatic (Paper 1). P fimbriae enhanced the establishment of bacteria in the human urinary tract. P fimbriated transformants of the ABU strain (E. coli 83972pap+/prs+) reached 105 CFU/ml more rapidly than E. coli 83972 and the vector control. This was demonstrated by group wise and intra-individual analysis, in patients colonized on different occasions with E. coli 83972 or the P fimbriated transformants (Paper 2). P fimbriated E. coli triggered the host response more efficiently than the ABU strain. Higher neutrophil numbers and IL-8 and IL-6 concentrations in urine were obtained after colonization with the P fimbriated transformants. These results demonstrated that transformation of E. coli 83972 with the pap sequences is sufficient to convert it to a more potent host response inducer (Paper 3). The P fimbriae were shown to lower the significant bacteriuria threshold. The P fimbriated transformants needed lower bacterial numbers (103-4 CFU/ml) to predict a positive second urine culture with a > 80% accuracy and to trigger a significant host response (Paper 4). The expression of P fimbriae in vivo was monitored using a gfp reporter gene construct. Following inoculation, E. coli 83972pap+ gfp+ adhered to the uroepithelial cells. A host response was triggered, and the cells were cleared from adherent bacteria. In parallell, neutrophils containing GFP protein were detected. The results demonstrated that P fimbriae mediate adherence in the human urinary tract, and illustrate the complex interaction with the host response exemplified by neutrophils (Paper 5). These studies show that P fimbriae fulfil the Koch Henles molecular postulates for bacterial establishment and host response induction in the human urinary tract.
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| 4. |
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| 5. |
- Svanborg, Catharina, et al.
(författare)
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Adhesion, signal transduction and mucosal inflammation
- 2002
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Ingår i: Bacterial Adhesion to Host Tissues. - Cambridge : Cambridge University Press. - 9780521801072 - 0521801079 ; , s. 223-246
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 6. |
- Grönberg Hernandez, Jenny, et al.
(författare)
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Genetic control of the variable innate immune response to asymptomatic bacteriuria.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:11
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Tidskriftsartikel (refereegranskat)abstract
- 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-α, RANTES, Eotaxin-1 and MCP-1, the T cell chemoattractant and antibacterial peptide IP-10, inflammatory regulators IL-1-α and sIL-1RA and the T lymphocyte/dendritic cell product sIL-2Rα 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-2Rα 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.
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| 7. |
- Hallgren, Oskar, et al.
(författare)
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Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).
- 2008
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer New York. - 0065-2598. ; 606, s. 217-240
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Forskningsöversikt (refereegranskat)abstract
- HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.
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| 8. |
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| 9. |
- Samuelsson, Patrik, et al.
(författare)
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Toll-like receptor 4 expression and cytokine responses in the human urinary tract mucosa.
- 2004
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Ingår i: Infection and Immunity. - 1098-5522. ; 72:6, s. 3179-3186
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal pathogens trigger a local innate host response by activating epithelial cells. Bacterial adherence and Toll-like receptor 4 (TLR4) signaling have been implicated as key events in this process. This study addressed the molecular basis of the epithelial response to gram-negative infection in the human urinary tract. Mucosal biopsies were obtained from kidneys, ureters, and bladders of patients undergoing urinary tract surgery, and epithelial TLR4 and CD14 expression was examined by immunohistochemistry. TLR4 was detected in epithelial cells lining the entire urinary tract and in the renal tubular epithelium. CD14, in contrast, was completely absent from the epithelial tissue. The response of the epithelial cells to infection was studied by in vitro challenge of the biopsies with uropathogenic Escherichia coli bacteria. A rapid cytokine response was observed, with production of interleukin-1ß (IL-1ß), IL-6, and IL-8 but not of IL-4 or gamma interferon. Adhering, P- or type 1-fimbriated E. coli activated IL-6 and IL-8 production more efficiently than the nonfimbriated control, as shown by cellular staining and analysis of secreted cytokines. The results demonstrate that human uroepithelial cells possess the molecular machinery needed to respond to uropathogenic E. coli. This includes recognition receptors for fimbriae and TLR4 for transmembrane signaling. We speculate that the lack of membrane-bound CD14 allows the epithelium to regulate its sensitivity to lipopolysaccharide and to discriminate between more-virulent and less-virulent strains.
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| 10. |
- Zdziarski, J, et al.
(författare)
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Molecular basis of commensalism in the urinary tract: low virulence or virulence attenuation?
- 2008
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Ingår i: Infection and Immunity. - 1098-5522. ; 76:2, s. 695-703
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Tidskriftsartikel (refereegranskat)abstract
- In some patients Escherichia coli strains establish significant bacteriuria without causing symptoms of urinary tract infection (UTI). These asymptomatic bacteriuria (ABU) strains have been shown to express fewer virulence factors than the uropathogenic E. coli (UPEC) strains that cause severe, symptomatic UTI. Paradoxically, ABU strains carry many typical UPEC virulence genes, however, and the molecular basis of their low virulence therefore remains unclear. This study examined if ABU strains may evolve from UPEC by genome loss and virulence gene attenuation. The presence of conserved E. coli K-12 genes was examined using an E. coli K-12 strain MG1655-specific DNA array and the distribution of UPEC virulence-related genes with the E. coli pathoarray. Two groups of strains could be distinguished. Several ABU strains were shown by multi locus sequence typing and by comparative genomic analyses to be related to UPEC but to have smaller genome sizes. There were significant alterations in essential virulence genes, including reductive evolution by point mutations, DNA rearrangements and deletions. Other strains were unrelated to UPEC and lacked most of the virulence-associated genes. The results suggest that some ABU strains arise from virulent strains by attenuation of virulence genes while others are non-virulent and resemble commensal strains. We propose that virulence attenuation might constitute a general mechanism for mucosal pathogens to evolve towards commensalism.
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