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Journal articleWarris A, Bercusson A, Armstrong-James D, 2019,
Aspergillus colonization and antifungal immunity in cystic fibrosis patients
, MEDICAL MYCOLOGY, Vol: 57, Pages: S118-S126, ISSN: 1369-3786- Author Web Link
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- Citations: 17
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Journal articleMaurice JB, Garvey L, Tsochatzis EA, et al., 2019,
Monocyte-macrophage activation is associated with nonalcoholic fatty liver disease and liver fibrosis in HIV monoinfection independently of the gut microbiome and bacterial translocation.
, AIDS, Vol: 33, Pages: 805-814, ISSN: 0269-9370BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is common among people living with HIV. There are limited data available on the pathophysiology of NAFLD and the development of fibrosis in this population. OBJECTIVES: The aim of this study was to investigate the association of bacterial translocation, adipose tissue dysfunction, monocyte activation and gut dysbiosis in patients with HIV monoinfection and NAFLD. METHODS: Cases with biopsy-proven NAFLD and HIV monoinfection were age and sex-matched to HIV-positive and HIV-negative controls. Markers of bacterial translocation [lipopolysaccharide-binding protein (LBP), bacterial DNA and lipopolysaccharide (LPS)], adipose tissue dysfunction (leptin, adiponectin) and monocyte activation (sCD14 and sCD163) were measured by ELISA. Hepatic patterns of macrophage activation were explored with immunohistochemistry. 16 s rRNA sequencing was performed with stool. RESULTS: Thirty-three cases were included (≥F2 fibrosis n = 16), matched to HIV-positive (n = 29) and HIV-negative (n = 17) controls. Cases with NAFLD were more obese (BMI 31.0 ± 4.4 vs. 24.1 ± 2.8 kg/m, P < 0.001) and had significantly increased levels of sCD14, sCD163 and higher leptin to adiponectin ratio vs. HIV-positive controls. Cases with ≥F2 verses < F2 fibrosis had increased sCD14 (1.4 ± 0.4 vs. 1.1 ± 0.3 μg/ml, P = 0.023) and sCD163 (1.0 ± 0.3 vs. 0.8 ± 0.3 μg/ml, P = 0.060), which correlated with waist circumference (sCD14 P = 0.022, sCD163 P = 0.011). Immunohistochemistry showed increased hepatic portal macrophage clusters in patients with fibrosis. No markers of bacterial translocation or changes to the microbiome were associated with NAFLD or fibrosis. CONCLUSION: NAFLD fibrosis stage in HIV monoinfected patients is associated with monocyte activation in the context of obesity, which may be independent of bacterial translocation and gut microbiome.
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Journal articleZhang P, Wang Z, Zhao S, et al., 2019,
H-1, C-13 and N-15 NMR assignments of Bacillus subtilis bacteriophage SPO1 protein Gp46
, BIOMOLECULAR NMR ASSIGNMENTS, Vol: 13, Pages: 245-247, ISSN: 1874-2718- Author Web Link
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- Citations: 3
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Journal articleMiliara X, Tatsuta T, Berry J-L, et al., 2019,
Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins
, Nature Communications, Vol: 10, Pages: 1-15, ISSN: 2041-1723Conserved lipid transfer proteins of the Ups/PRELI family regulate lipid accumulation in mitochondria by shuttling phospholipids in a lipid-specific manner across the intermembrane space. Here, we combine structural analysis, unbiased genetic approaches in yeast and molecular dynamics simulations to unravel determinants of lipid specificity within the conserved Ups/PRELI family. We present structures of human PRELID1–TRIAP1 and PRELID3b–TRIAP1 complexes, which exert lipid transfer activity for phosphatidic acid and phosphatidylserine, respectively. Reverse yeast genetic screens identify critical amino acid exchanges that broaden and swap their lipid specificities. We find that amino acids involved in head group recognition and the hydrophobicity of flexible loops regulate lipid entry into the binding cavity. Molecular dynamics simulations reveal different membrane orientations of PRELID1 and PRELID3b during the stepwise release of lipids. Our experiments thus define the structural determinants of lipid specificity and the dynamics of lipid interactions by Ups/PRELI proteins.
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Journal articleLorenz A, Preusse M, Bruchmann S, et al., 2019,
Importance of flagella in acute and chronic Pseudomonas aeruginosa infections
, Environmental Microbiology, Vol: 21, Pages: 883-897, ISSN: 1462-2912Pseudomonas aeruginosa is an environmental microorganism and a causative agent of diverse acute and chronic, biofilm‐associated infections. Advancing research‐based knowledge on its adaptation to conditions within the human host is bound to reveal novel strategies and targets for therapeutic intervention. Here, we investigated the traits that P. aeruginosa PA14 as well as a virulence attenuated ΔlasR mutant need to survive in selected murine infection models. Experimentally, the genetic programs that the bacteria use to adapt to biofilm‐associated versus acute infections were dissected by passaging transposon mutant libraries through mouse lungs (acute) or mouse tumours (biofilm‐infection). Adaptive metabolic changes of P. aeruginosa were generally required during both infection processes. Counter‐selection against flagella expression was observed during acute lung infections. Obviously, avoidance of flagella‐mediated activation of host immunity is advantageous for the wildtype bacteria. For the ΔlasR mutant, loss of flagella did not confer a selective advantage. Apparently, other pathogenesis mechanisms are active in this virulence attenuated strain. In contrast, the infective process of P. aeruginosa in the chronic biofilm model apparently required expression of flagellin. Together, our findings imply that the host immune reactions against the infectious agent are very decisive for acuteness and duration of the infectious disease. They direct disease outcome.
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Journal articleYu L-S, Rodriguez-Manzano J, Malpartida-Cardenas K, et al., 2019,
Rapid and sensitive detection of azole-resistant Aspergillus fumigatus by tandem-repeat loop-mediated isothermal amplification
, Journal of Molecular Diagnostics, Vol: 21, Pages: 286-295, ISSN: 1525-1578Invasive human fungal infections caused by multi-azole resistant Aspergillus fumigatus are associated with increasing rates of mortality in susceptible patients. Current methods of diagnosing infections caused by multi-azole resistant A. fumigatus are, however, not well suited for use in clinical point-of-care testing or in the field. Loop-mediated isothermal amplification (LAMP) is a widely used method of nucleic acid amplification with rapid and easy-to-use features, making it suitable for use in different resource settings. Here, we developed a LAMP assay to detect a 34 bp tandem repeat, named TR34-LAMP. TR34 is a high-prevalence allele that, in conjunction with the L98H single nucleotide polymorphism, is associated with the occurrence of multi-azole resistance in A. fumigatus in the environment and in patients. This process was validated with both synthetic double stranded DNA and genomic DNA prepared from azole-resistant isolates of A. fumigatus. Use of our assay resulted in rapid and specific identification of the TR34 allele with high sensitivity, detecting down to 10 genomic copies per reaction within 25 minutes. Fluorescent and colorimetric detections were used for the analysis of 11 clinical isolates as cross validation. These results show that the TR34-LAMP assay has the potential to accelerate the screening of clinical and environmental A. fumigatus to provide a rapid and accurate diagnosis of azole resistance, which current methods struggle to achieve.
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Journal articleFilloux A, Davies JC, 2019,
Chronic infection by controlling inflammation
, NATURE MICROBIOLOGY, Vol: 4, Pages: 378-379, ISSN: 2058-5276 -
Conference paperOvadia C, Perdones-Montero A, Mullish B, et al., 2019,
Ursodeoxycholic acid treatment of cholestatic pregnancy can alter the gut microbiota to enhance bile acid modification and production of metabolically-active secondary bile acids - an explanation for 'responders' and 'non-responders'?
, Publisher: WILEY, Pages: 17-17, ISSN: 1470-0328 -
Journal articleTenland E, Pochert A, Krishnan N, et al., 2019,
Effective delivery of the anti-mycobacterial peptide NZX in mesoporous silica nanoparticles
, PLoS ONE, Vol: 14, ISSN: 1932-6203BackgroundIntracellular delivery of antimicrobial agents by nanoparticles, such as mesoporous silica particles (MSPs), offers an interesting strategy to treat intracellular infections. In tuberculosis (TB), Mycobacterium tuberculosis avoids components of the immune system by residing primarily inside alveolar macrophages, which are the desired target for TB therapy.Methods and findingsWe have previously identified a peptide, called NZX, capable of inhibiting both clinical and multi-drug resistant strains of M. tuberculosis at therapeutic concentrations. In this study we analysed the potential of MSPs containing NZX for the treatment of tuberculosis. The MSPs released functional NZX gradually into simulated lung fluid and the peptide filled MSPs were easily taken up by primary macrophages. In an intracellular infection model, the peptide containing particles showed increased mycobacterial killing compared to free peptide. The therapeutic potential of peptide containing MSPs was investigated in a murine infection model, showing that MSPs preserved the effect to eliminate M. tuberculosis in vivo.ConclusionsIn this study we found that loading the antimicrobial peptide NZX into MSPs increased the inhibition of intracellular mycobacteria in primary macrophages and preserved the ability to eliminate M. tuberculosis in vivo in a murine model. Our studies provide evidence for the feasibility of using MSPs for treatment of tuberculosis.
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Journal articleLevanova N, Mattheis C, Carson D, et al., 2019,
The Legionella effector LtpM is a new type of phosphoinositide-activated glucosyltransferase
, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 294, Pages: 2862-2879
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