| 1. |
- Ambite, Ines, et al.
(författare)
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Molecular Basis of Acute Cystitis Reveals Susceptibility Genes and Immunotherapeutic Targets
- 2016
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Tissue damage is usually regarded as a necessary price to pay for successful elimination of pathogens by the innate immune defense. Yet, it is possible to distinguish protective from destructive effects of innate immune activation and selectively attenuate molecular nodes that create pathology. Here, we identify acute cystitis as an Interleukin-1 beta (IL-1β)-driven, hyper-inflammatory condition of the infected urinary bladder and IL-1 receptor blockade as a novel therapeutic strategy. Disease severity was controlled by the mechanism of IL-1β processing and mice with intact inflammasome function developed a moderate, self-limiting form of cystitis. The most severe form of acute cystitis was detected in mice lacking the inflammasome constituents ASC or NLRP-3. IL-1β processing was hyperactive in these mice, due to a new, non-canonical mechanism involving the matrix metalloproteinase 7- (MMP-7). ASC and NLRP-3 served as transcriptional repressors of MMP7 and as a result, Mmp7 was markedly overexpressed in the bladder epithelium of Asc-/- and Nlrp3-/- mice. The resulting IL-1β hyper-activation loop included a large number of IL-1β-dependent pro-inflammatory genes and the IL-1 receptor antagonist Anakinra inhibited their expression and rescued susceptible Asc-/- mice from bladder pathology. An MMP inhibitor had a similar therapeutic effect. Finally, elevated levels of IL-1β and MMP-7 were detected in patients with acute cystitis, suggesting a potential role as biomarkers and immunotherapeutic targets. The results reproduce important aspects of human acute cystitis in the murine model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common infections in man. Trial Registration: The clinical studies were approved by the Human Ethics Committee at Lund University (approval numbers LU106-02, LU236-99 and Clinical Trial Registration RTP-A2003, International Committee of Medical Journal Editors, www.clinicaltrials.gov).
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| 2. |
- Ambite, Ines, et al.
(författare)
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The Genetics of Urinary Tract Infections and the Innate Defense of the Kidney and Urinary tract
- 2016
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Ingår i: Journal of pediatric genetics. - : Georg Thieme Verlag KG. - 2146-4596 .- 2146-460X. ; 5:1, s. 25-32
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Forskningsöversikt (refereegranskat)abstract
- The urinary tract is a sterile organ system. Urinary tract infections (UTIs) are common and often serious infections. Research has focused on uropathogen, environment, and host factors leading to UTI pathogenesis. A growing body of evidence exists implicating genetic factors that can contribute to UTI risks. In this review, we highlight genetic variations in aspects of the innate immune system critical to the host response to uropathogens. This overview includes genetic variations in pattern recognition receptor molecules, chemokines/cytokines, and neutrophil activation. We also comprehensively cover murine knockout models of UTI, genetic variations involved in renal scarring as a result of ascending UTIs, and asymptomatic bacteriuria.
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| 3. |
- Chauvin, Maxime, et al.
(författare)
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Observation of polarized hard X-ray emission from the Crab by the PoGOLite Pathfinder
- 2016
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966 .- 1745-3925 .- 1745-3933. ; 456:1, s. L84-L88
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Tidskriftsartikel (refereegranskat)abstract
- We have measured the linear polarization of hard X-ray emission from the Crab in a previously unexplored energy interval, 20-120 keV. The introduction of two new observational parameters, the polarization fraction and angle stands to disentangle geometrical and physical effects, thereby providing information on the pulsar wind geometry and magnetic field environment. Measurements are conducted using the PoGOLite Pathfinder - a balloon-borne polarimeter. Polarization is determined by measuring the azimuthal Compton scattering angle of incident X-rays in an array of plastic scintillators housed in an anticoincidence well. The polarimetric response has been characterized prior to flight using both polarized and unpolarized calibration sources. We address possible systematic effects through observations of a background field. The measured polarization fraction for the integrated Crab light curve is 18.4(-10.6)(+9.8) per cent, corresponding to an upper limit (99 per cent credibility) of 42.4 per cent, for a polarization angle of (149.2 +/- 16.0)degrees.
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| 4. |
- Chauvin, Maxime, et al.
(författare)
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The design and flight performance of the PoGOLite Pathfinder balloon-borne hard X-ray polarimeter
- 2016
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Ingår i: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 41:1, s. 17-41
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Tidskriftsartikel (refereegranskat)abstract
- In the 50 years since the advent of X-ray astronomy there have been many scientific advances due to the development of new experimental techniques for detecting and characterising X-rays. Observations of X-ray polarisation have, however, not undergone a similar development. This is a shortcoming since a plethora of open questions related to the nature of X-ray sources could be resolved through measurements of the linear polarisation of emitted X-rays. The PoGOLite Pathfinder is a balloon-borne hard X-ray polarimeter operating in the 25-240 keV energy band from a stabilised observation platform. Polarisation is determined using coincident energy deposits in a segmented array of plastic scintillators surrounded by a BGO anticoincidence system and a polyethylene neutron shield. The PoGOLite Pathfinder was launched from the SSC Esrange Space Centre in July 2013. A near-circumpolar flight was achieved with a duration of approximately two weeks. The flight performance of the Pathfinder design is discussed for the three Crab observations conducted. The signal-to-background ratio for the observations is shown to be 0.25 ±0.03 and the Minimum Detectable Polarisation (99 % C.L.) is (28.4 ±2.2) %. A strategy for the continuation of the PoGOLite programme is outlined based on experience gained during the 2013 maiden flight.
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| 5. |
- Godaly, Gabriela, et al.
(författare)
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Urinary Tract Infection Molecular Mechanisms and Clinical Translation.
- 2016
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Ingår i: Pathogens. - : MDPI AG. - 2076-0817. ; 5:1
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Forskningsöversikt (refereegranskat)abstract
- 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 pathways that define symptoms and pathology and the genetic control of innate immune responses that balance protection against tissue damage. For some of these genes, human relevance has been documented in clinical studies, identifying them as potential targets for immune-modulatory therapies, as a complement to antibiotics.
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| 6. |
- Kiss, Mózsi, et al.
(författare)
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The PoGOLite balloon-borne soft gamma-ray polarimeter
- 2008
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Ingår i: COOL DISCS, HOT FLOWS. - : AIP. ; , s. 225-232
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Konferensbidrag (refereegranskat)abstract
- Linearly polarized radiation in the hard X-ray/soft gamma-ray band is expected from a large variety of astronomical sources. We discuss the importance of polarimetric studies for several classes of sources - pulsars, accreting black holes. magnetic neutron stars and jets from active galaxies - and then describe PoGOLite, a balloon-borne instrument which is currently under construction and will be able to measure the polarization of electromagnetic radiation from such extra-solar objects in the energy range 25-80 keV.
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| 7. |
- Nilsson, Tobias, et al.
(författare)
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Lipid-mediated Protein-protein Interactions Modulate Respiration-driven ATP Synthesis
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Energy conversion in biological systems is underpinned by membrane-bound proton transporters that generate and maintain a proton electrochemical gradient across the membrane which used, e.g. for generation of ATP by the ATP synthase. Here, we have co-reconstituted the proton pump cytochrome bo3 (ubiquinol oxidase) together with ATP synthase in liposomes and studied the effect of changing the lipid composition on the ATP synthesis activity driven by proton pumping. We found that for 100 nm liposomes, containing 5 of each proteins, the ATP synthesis rates decreased significantly with increasing fractions of DOPA, DOPE, DOPG or cardiolipin added to liposomes made of DOPC; with e.g. 5% DOPG, we observed an almost 50% decrease in the ATP synthesis rate. However, upon increasing the average distance between the proton pumps and ATP synthases, the ATP synthesis rate dropped and the lipid dependence of this activity vanished. The data indicate that protons are transferred along the membrane, between cytochrome bo3 and the ATP synthase, but only at sufficiently high protein densities. We also argue that the local protein density may be modulated by lipid-dependent changes in interactions between the two proteins complexes, which points to a mechanism by which the cell may regulate the overall activity of the respiratory chain.
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| 8. |
- Nordlund, Gustav, 1980-, et al.
(författare)
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Effect of lipid composition on respiration-driven ATP synthesis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Energy conversion in biological systems is underpinned by membrane-bound proton transporters that generate and maintain a proton electrochemical gradient across the membrane. The free energy stored in this gradient is used, for example, for transport of molecules or ions by other transporters as well as for generation of ATP by the ATP synthase. Understanding the overall process requires functional studies of the coupled reactions, which involve co-reconstitution of e.g. a proton pump and a transporter that utilizes the proton gradient. This process is likely to be further influenced by the composition of the membrane, which, for example, may facilitate lateral proton transfer. In the present study, we have co-reconstituted the proton pump bo3 ubiquinol oxidase with ATP synthase, both from E. coli, in liposomes with different membrane compositions. The coupled proton pumping and ATP-synthesis activities were investigated. We found that the ATP synthesis was significantly higher in a membrane composed of pure DOPC lipids than in the presence of DOPA, DOPE, DOPG or cardiolipin. The drop in activity was considerably more pronounced upon addition of the negatively charged head groups (PA, PG or cardiolipin) than upon addition of the zwitterionic PE. The origin of these effects is discussed.
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| 9. |
- Puthia, Manoj, et al.
(författare)
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IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:336
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Tidskriftsartikel (refereegranskat)abstract
- 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, andIFNB1 promoter oligonucleotides. These data are consistent in children with lowIRF7 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.
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