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  • Journal article
    Vivian T, Yi L, Ashleigh C, Larrouy-Maumus Get al., 2021,

    Metabolomics in infectious diseases and drug discovery

    , Molecular Omics, Vol: 17, Pages: 376-393, ISSN: 2515-4184

    Metabolomics has emerged as an invaluable tool that can be used along with genomics, transcriptomics and proteomics to understand host–pathogen interactions at small-molecule levels. Metabolomics has been used to study a variety of infectious diseases and applications. The most common application of metabolomics is for prognostic and diagnostic purposes, specifically the screening of disease-specific biomarkers by either NMR-based or mass spectrometry-based metabolomics. In addition, metabolomics is of great significance for the discovery of druggable metabolic enzymes and/or metabolic regulators through the use of state-of-the-art flux analysis, for example, via the elucidation of metabolic mechanisms. This review discusses the application of metabolomics technologies to biomarker screening, the discovery of drug targets in infectious diseases such as viral, bacterial and parasite infections and immunometabolomics, highlights the challenges associated with accessing metabolite compartmentalization and discusses the available tools for determining local metabolite concentrations.
  • Journal article
    Bakovic J, Yu BYK, Silva D, Baczynska M, Peak-Chew SY, Switzer A, Burchell L, Wigneshweraraj S, Vandanashree M, Gopal B, Filonenko V, Skehel M, Gout Iet al., 2021,

    Redox Regulation of the Quorum-sensing Transcription Factor AgrA by Coenzyme A

    , ANTIOXIDANTS, Vol: 10
  • Journal article
    Gonzalo X, Broda A, Drobniewski F, Larrouy-Maumus Get 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: 1198-743X

    ObjectivesBacterial 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
  • Journal article
    Steinchen W, Ahmad S, Valentini M, Eilers K, Majkini M, Altegoer F, Lechner M, Filloux A, Whitney JC, Bange Get al., 2021,

    Dual role of a (p)ppGpp- and (p)ppApp-degrading enzyme in biofilm formation and interbacterial antagonism

    , Molecular Microbiology, Vol: 115, Pages: 1339-1356, ISSN: 0950-382X

    The guanosine nucleotide‐based second messengers ppGpp and pppGpp (collectively: (p)ppGpp) enable adaptation of microorganisms to environmental changes and stress conditions. In contrast, the closely related adenosine nucleotides (p)ppApp are involved in type VI secretion system (T6SS)‐mediated killing during bacterial competition. Long RelA‐SpoT Homolog (RSH) enzymes regulate synthesis and degradation of (p)ppGpp (and potentially also (p)ppApp) through their synthetase and hydrolase domains, respectively. Small alarmone hydrolases (SAH) that consist of only a hydrolase domain are found in a variety of bacterial species, including the opportunistic human pathogen Pseudomonas aeruginosa. Here, we present the structure and mechanism of P. aeruginosa SAH showing that the enzyme promiscuously hydrolyses (p)ppGpp and (p)ppApp in a strictly manganese‐dependent manner. While being dispensable for P. aeruginosa growth or swimming, swarming, and twitching motilities, its enzymatic activity is required for biofilm formation. Moreover, (p)ppApp‐degradation by SAH provides protection against the T6SS (p)ppApp synthetase effector Tas1, suggesting that SAH enzymes can also serve as defense proteins during interbacterial competition.
  • Journal article
    Chisenga CC, Bosomprah S, Simuyandi M, Mwila-Kazimbaya K, Chilyabanyama ON, Laban NM, Bialik A, Asato V, Meron-Sudai S, Frankel G, Cohen D, Chilengi Ret 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
  • Journal article
    Yebra G, Haag AF, Neamah MM, Wee BA, Richardson EJ, Horcajo P, Granneman S, Angeles Tormo-Mas M, de la Fuente R, Fitzgerald JR, Penades JRet al., 2021,

    Radical genome remodelling accompanied the emergence of a novel host-restricted bacterial pathogen

    , PLoS Pathogens, Vol: 17, Pages: 1-23, ISSN: 1553-7366

    The 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.
  • Conference paper
    Miguens Blanco J, Liu Z, Mullish BH, Danckert NP, Alexander JL, Chrysostomou D, Sengupta R, McHugh N, McDonald JAK, Abraham SM, Marchesi JRet al., 2021,

    A Phenomic Characterization of the Gut Microbiota - Associations with Psoriatic Arthritis and Ankylosing Spondylitis

    , World Microbe Forum
  • Book chapter
    Larrouy-Maumus G, 2021,

    Shotgun bacterial lipid A analysis using routine MALDI-TOF mass spectrometry.

    , Mass Spectrometry-Based Lipidomics, Editors: Hsu, Pages: 275-283

    Detection 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.
  • Journal article
    Mylona E, Sanchez Garrido J, Nguyen Hoang Thu T, Dongol S, Karkey A, Baker S, Shenoy AR, Frankel Get 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: 1462-5814

    Salmonella 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.
  • Journal article
    Padayachee Y, Faiez TS, Singanayagam A, Mallia P, Johnston SLet al., 2021,

    Asthma and viruses: A focus on rhinoviruses and SARS-CoV-2

    , JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 147, Pages: 1648-1651, ISSN: 0091-6749

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