1.
Ambite, Inès, et al.
(författare)
Active bacterial modification of the host environment through RNA polymerase II inhibition
2021
Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 131:4
Tidskriftsartikel (refereegranskat) abstract
Unlike pathogens, which attack the host, commensal bacteria create a state of friendly coexistence. Here, we identified a mechanism of bacterial adaptation to the host niche, where they reside. Asymptomatic carrier strains were shown to inhibit RNA polymerase II (Pol II) in host cells by targeting Ser2 phosphorylation, a step required for productive mRNA elongation. Assisted by a rare, spontaneous loss-of-function mutant from a human carrier, the bacterial NlpD protein was identified as a Pol II inhibitor. After internalization by host cells, NlpD was shown to target constituents of the Pol II phosphorylation complex (RPB1 and PAF1C), attenuating host gene expression. Therapeutic efficacy of a recombinant NlpD protein was demonstrated in a urinary tract infection model, by reduced tissue pathology, accelerated bacterial clearance, and attenuated Pol II-dependent gene expression. The findings suggest an intriguing, evolutionarily conserved mechanism for bacterial modulation of host gene expression, with a remarkable therapeutic potential.
2.
Garau, Javier, et al.
(författare)
Antibiotic stewardship challenges in the management of community-acquired infections for prevention of escalating antibiotic resistance
2014
Ingår i: Journal of Global Antimicrobial Resistance. - : Elsevier BV. - 2213-7165. ; 2:4, s. 245-253
Forskningsöversikt (refereegranskat) abstract
Community-acquired infections, including respiratory tract infections (RTIs) and urinary tract infections (UTIs), represent a major burden for most healthcare systems, partially due to ineffective or inappropriate antibiotic treatment leading to clinical failure, which often requires alternative antibiotics for cure. Appropriate antimicrobial use not only maximises clinical success in the treatment of community-acquired infections, but also minimises unintended consequences such as resistance development or collateral damage. This article outlines a range of antibiotic stewardship strategies and other preventative approaches that support the management of community-acquired infections, based on existing antibiotic use for community-acquired infections and the current resistance patterns among common RTI and UTI pathogens. (C) 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Chemotherapy of Infection and Cancer.
3.
4.
Grönberg Hernandez, Jenny, et al.
(författare)
Genetic control of the variable innate immune response to asymptomatic bacteriuria.
2011
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:11
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.
5.
Hallgren, Oskar, et al.
(författare)
Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).
2008
Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer New York. - 0065-2598. ; 606, s. 217-240
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.
6.
Lutay, Nataliya, et al.
(författare)
Bacterial control of host gene expression through RNA polymerase II
2013
Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 123:6, s. 2366-2379
Tidskriftsartikel (refereegranskat) abstract
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 coil 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 II-dependent (Pol II-dependent) host gene expression. Over 60% of all genes were suppressed 24 hours after human inoculation with the prototype asymptomatic bacteriuria (ABU) strain E. coil 83972, and inhibition was verified by infection of human cells. Specific repressors and activators of Pol II-dependent 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.
7.
Ragnarsdottir, Bryndis, et al.
(författare)
TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections.
2008
Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 38 Suppl 2, s. 12-20
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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9.
Samuelsson, Patrik, et al.
(författare)
Toll-like receptor 4 expression and cytokine responses in the human urinary tract mucosa.
2004
Ingår i: Infection and Immunity. - 1098-5522. ; 72:6, s. 3179-3186
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.
10.
