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Journal articleGonzalo X, Broda A, Drobniewski F, et al., 2021,
Performance of lipid fingerprint-based MALDI-ToF for the diagnosis of mycobacterial infections
, Clinical Microbiology and Infection, Vol: 27, Pages: 912.e1-912.e5, ISSN: 1198-743XObjectivesBacterial diagnosis of mycobacteria is often challenging because of the variability of the sensitivity and specificity of the assay used, and it can be expensive to perform accurately. Although matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) has become the workhorse of clinical laboratories, the current MALDI methodology (which is based on cytosolic protein profiling) for mycobacteria is still challenging due to the number of steps involved (up to seven) and potential biosafety concerns. Knowing that mycobacteria produce surface-exposed species-specific lipids, we here hypothesized that the detection of those molecules could offer a rapid, reproducible and robust method for mycobacterial identification.MethodsWe evaluated the performance of an alternative methodology based on characterized species-specific lipid profiling of intact bacteria, without any sample preparation, by MALDI MS; it uses MALDI-time-of-flight (ToF) MS combined with a specific matrix (super-2,5-dihydroxybenzoic acid solubilized in an apolar solvent system) to analyse lipids of intact heat-inactivated mycobacteria. Cultured mycobacteria are heat-inactivated and loaded directly onto the MALDI target followed by addition of the matrix. Acquisition of the data is done in both positive and negative ion modes. Blinded studies were performed using 273 mycobacterial strains comprising both the Mycobacterium tuberculosis (Mtb) complex and non-tuberculous mycobacteria (NTMs) subcultured in Middlebrook 7H9 media supplemented with 10% OADC (oleic acid/dextrose/catalase) growth supplement and incubated for up to 2 weeks at 37°C.ResultsThe method we have developed is fast (<10 mins) and highly sensitive (<1000 bacteria required); 96.7% of the Mtb complex strains (204/211) were correctly assigned as MTB complex and 91.7% (22/24) NTM species were correctly assigned based only on intact bacteria species-specific lipid profiling by MALDI-ToF MS.ConclusionsIntact bacter
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Journal articleChisenga CC, Bosomprah S, Simuyandi M, et al., 2021,
Shigella-specific antibodies in the first year of life among Zambian infants: A longitudinal cohort study
, PLOS ONE, Vol: 16, ISSN: 1932-6203- Author Web Link
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- Citations: 5
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Journal articleYebra G, Haag AF, Neamah MM, et al., 2021,
Radical genome remodelling accompanied the emergence of a novel host-restricted bacterial pathogen
, PLoS Pathogens, Vol: 17, Pages: 1-23, ISSN: 1553-7366The emergence of new pathogens is a major threat to public and veterinary health. Changes in bacterial habitat such as a switch in host or disease tropism are typically accompanied by genetic diversification. Staphylococcus aureus is a multi-host bacterial species associated with human and livestock infections. A microaerophilic subspecies, Staphylococcus aureus subsp. anaerobius, is responsible for Morel’s disease, a lymphadenitis restricted to sheep and goats. However, the evolutionary history of S. aureus subsp. anaerobius and its relatedness to S. aureus are unknown. Population genomic analyses of clinical S. aureus subsp. anaerobius isolates revealed a highly conserved clone that descended from a S. aureus progenitor about 1000 years ago before differentiating into distinct lineages that contain African and European isolates. S. aureus subsp. anaerobius has undergone limited clonal expansion, with a restricted population size, and an evolutionary rate 10-fold slower than S. aureus. The transition to its current restricted ecological niche involved acquisition of a pathogenicity island encoding a ruminant host-specific effector of abscess formation, large chromosomal re-arrangements, and the accumulation of at least 205 pseudogenes, resulting in a highly fastidious metabolism. Importantly, expansion of ~87 insertion sequences (IS) located largely in intergenic regions provided distinct mechanisms for the control of expression of flanking genes, including a novel mechanism associated with IS-mediated anti-anti-sense decoupling of ancestral gene repression. Our findings reveal the remarkable evolutionary trajectory of a host-restricted bacterial pathogen that resulted from extensive remodelling of the S. aureus genome through an array of diverse mechanisms in parallel.
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Conference paperMiguens Blanco J, Liu Z, Mullish BH, et al., 2021,
A Phenomic Characterization of the Gut Microbiota - Associations with Psoriatic Arthritis and Ankylosing Spondylitis
, World Microbe Forum -
Book chapterLarrouy-Maumus G, 2021,
Shotgun bacterial lipid A analysis using routine MALDI-TOF mass spectrometry.
, Mass Spectrometry-Based Lipidomics, Editors: Hsu, Pages: 275-283Detection of bacterial lipids and particularly the lipid A, the lipid anchor of the lipopolysaccharide, can be very challenging and requires a certain level of expertise. Here, this chapter describes a straightforward and simple method for the analysis of bacterial lipid A. In addition, such approach, lipid fingerprint, has the potential to be applied to other bacteria such as mycobacteria.
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Journal articlePanwar RB, Sequeira RP, Clarke TB, 2021,
Microbiota-mediated protection against antibiotic-resistant pathogens
, GENES AND IMMUNITY, Vol: 22, Pages: 255-267, ISSN: 1466-4879- Author Web Link
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- Citations: 3
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Journal articleBorah K, Mendum TA, Hawkins ND, et al., 2021,
Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis
, MOLECULAR SYSTEMS BIOLOGY, Vol: 17, ISSN: 1744-4292- Author Web Link
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- Citations: 8
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Journal articleMylona E, Sanchez Garrido J, Nguyen Hoang Thu T, et al., 2021,
Very long O-antigen chains of Salmonella Paratyphi A inhibit inflammasome activation and pyroptotic cell death
, Cellular Microbiology, Vol: 23, Pages: 1-14, ISSN: 1462-5814Salmonella Paratyphi A (SPtA) remains one of the leading causes of enteric (typhoid) fever. Yet, despite the recent increased rate of isolation from patients in Asia, our understanding of its pathogenesis is incomplete. Here we investigated inflammasome activation in human macrophages infected with SPtA. We found that SPtA induces GSDMD‐mediated pyroptosis via activation of caspase‐1, caspase‐4 and caspase‐8. Although we observed no cell death in the absence of a functional Salmonella pathogenicity island‐1 (SPI‐1) injectisome, HilA‐mediated overexpression of the SPI‐1 regulon enhances pyroptosis. SPtA expresses FepE, an LPS O‐antigen length regulator, which induces the production of very long O‐antigen chains. Using a ΔfepE mutant we established that the very long O‐antigen chains interfere with bacterial interactions with epithelial cells and impair inflammasome‐mediated macrophage cell death. Salmonella Typhimurium (STm) serovar has a lower FepE expression than SPtA, and triggers higher pyroptosis, conversely, increasing FepE expression in STm reduced pyroptosis. These results suggest that differential expression of FepE results in serovar‐specific inflammasome modulation, which mirrors the pro‐ and anti‐inflammatory strategies employed by STm and SPtA, respectively. Our studies point towards distinct mechanisms of virulence of SPtA, whereby it attenuates inflammasome‐mediated detection through the elaboration of very long LPS O‐polysaccharides.
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Journal articleBreyer F, Hartlova A, Thurston T, et al., 2021,
TPL-2 kinase induces phagosome acidification to promote macrophage killing of bacteria
, The EMBO Journal, Vol: 40, Pages: 1-19, ISSN: 0261-4189Tumour progression locus 2 (TPL-2) kinase mediates Toll-like receptor (TLR) activation of ERK1/2 and p38α MAP kinases in myeloid cells to modulate expression of key cytokines in innate immunity. This study identified a novel MAP kinase-independent regulatory function for TPL-2 in phagosome maturation, an essential process for killing of phagocytosed microbes. TPL-2 catalytic activity was demonstrated to induce phagosome acidification and proteolysis in primary mouse and human macrophages following uptake of latex beads. Quantitative proteomics revealed that blocking TPL-2 catalytic activity significantly altered the protein composition of phagosomes, particularly reducing the abundance of V-ATPase proton pump subunits. Furthermore, TPL-2 stimulated the phosphorylation of DMXL1, a regulator of V-ATPases, to induce V-ATPase assembly and phagosome acidification. Consistent with these results, TPL-2 catalytic activity was required for phagosome acidification and the efficient killing of Staphylococcus aureus and Citrobacter rodentium following phagocytic uptake by macrophages. TPL-2 therefore controls innate immune responses of macrophages to bacteria via V-ATPase induction of phagosome maturation.
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Journal articleGhani R, Mullish BH, McDonald JAK, et al., 2021,
Disease prevention not decolonization – a model for fecal microbiota transplantation in patients colonized with multidrug-resistant organisms
, Clinical Infectious Diseases, Vol: 72, Pages: 1444-1447, ISSN: 1058-4838Fecal microbiota transplantation (FMT) yields variable intestinal decolonization results for multidrug-resistant organisms (MDROs). This study showed significant reductions in antibiotic duration, bacteremia and length of stay in 20 patients colonized/ infected with MDRO receiving FMT (compared to pre-FMT history, and a matched group not receiving FMT), despite modest decolonization rates.
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