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  • Journal article
    Schulz LM, Rothe P, Halbedel S, Gründling A, Rismondo Jet al., 2022,

    Imbalance of peptidoglycan biosynthesis alters the cell surface charge of Listeria monocytogenes

    , The Cell Surface, Vol: 8, Pages: 1-16, ISSN: 2468-2330

    The bacterial cell wall is composed of a thick layer of peptidoglycan and cell wall polymers, which are either embedded in the membrane or linked to the peptidoglycan backbone and referred to as lipoteichoic acid (LTA) and wall teichoic acid (WTA), respectively. Modifications of the peptidoglycan or WTA backbone can alter the susceptibility of the bacterial cell towards cationic antimicrobials and lysozyme. The human pathogen Listeria monocytogenes is intrinsically resistant towards lysozyme, mainly due to deacetylation and O-acetylation of the peptidoglycan backbone via PgdA and OatA. Recent studies identified additional factors, which contribute to the lysozyme resistance of this pathogen. One of these is the predicted ABC transporter, EslABC. An eslB mutant is hyper-sensitive towards lysozyme, likely due to the production of thinner and less O-acetylated peptidoglycan. Using a suppressor screen, we show here that suppression of eslB phenotypes could be achieved by enhancing peptidoglycan biosynthesis, reducing peptidoglycan hydrolysis or alterations in WTA biosynthesis and modification. The lack of EslB also leads to a higher negative surface charge, which likely stimulates the activity of peptidoglycan hydrolases and lysozyme. Based on our results, we hypothesize that the portion of cell surface exposed WTA is increased in the eslB mutant due to the thinner peptidoglycan layer and that latter one could be caused by an impairment in UDP-N-acetylglucosamine (UDP-GlcNAc) production or distribution.

  • Journal article
    Powles STR, Gallagher KI, Chong LWL, Alexander JL, Mullish BH, Hicks LC, McDonald JAK, Marchesi JR, Williams HRT, Orchard TRet al., 2022,

    Effects of bowel preparation on intestinal bacterial associated urine and faecal metabolites and the associated faecal microbiome

    , BMC Gastroenterology, Vol: 22

    <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Urinary and faecal metabolic profiling have been extensively studied in gastrointestinal diseases as potential diagnostic markers, and to enhance our understanding of the intestinal microbiome in the pathogenesis these conditions. The impact of bowel cleansing on the microbiome has been investigated in several studies, but limited to just one study on the faecal metabolome.</jats:p> </jats:sec><jats:sec> <jats:title>Aim</jats:title> <jats:p>To compare the effects of bowel cleansing on the composition of the faecal microbiome, and the urine and faecal metabolome.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Urine and faecal samples were obtained from eleven patients undergoing colonoscopy at baseline, and then at day 3 and week 6 after colonoscopy. 16S rRNA gene sequencing was used to analyse changes in the microbiome, and metabonomic analysis was performed using proton nuclear magnetic resonance (<jats:sup>1</jats:sup>H NMR) spectroscopy.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Microbiomic analysis demonstrated a reduction in alpha diversity (Shannon index) between samples taken at baseline and three days following bowel cleansing (<jats:italic>p</jats:italic> = 0.002), and there was no significant difference between samples at baseline and six weeks post colonoscopy. Targeted and non-targeted analysis of urinary and faecal bacterial associated metabolites showed no significant impact following bowel cleansing.</jats:p> </jats:sec><jats:sec>

  • Journal article
    Mullish BH, Martinez Gili L, Chekmeneva E, Dos Santos Correia GDS, Lewis MR, Horneffer-van der Sluis V, Roberts LA, McDonald JAK, Pechlivanis A, Walters JRF, McClure EL, Marchesi JR, Allegretti JRet al., 2022,

    Assessing the clinical value of faecal bile acid profiling to predict recurrence in primary Clostridioides difficile infection

    , Alimentary Pharmacology and Therapeutics, Vol: 56, Pages: 1556-1569, ISSN: 0269-2813

    Background:Factors influencing recurrence risk in primary Clostridioides difficile infection (CDI) are poorly understood, and tools predicting recurrence are lacking. Perturbations in bile acids (BAs) contribute to CDI pathogenesis and may be relevant to primary disease prognosis.Aims:To define stool BA dynamics in patients with primary CDI and explore signatures predicting recurrenceMethodsWeekly stool samples were collected from patients with primary CDI from the last day of anti-CDI therapy until recurrence or, otherwise, through 8 weeks post-completion. Ultra-high performance liquid chromatography-mass spectrometry was used to profile BAs; stool bile salt hydrolase (BSH) activity was measured to determine primary BA bacterial deconjugation capacity. Multivariate and univariate models were used to define differential BA trajectories in patients with recurrence versus those without, and to assess faecal BAs as predictive markers for recurrence.Results:Twenty (36%) of 56 patients (median age: 57, 64% male) had recurrence; 80% of recurrences occurred within the first 9 days post-antibiotic treatment. Principal component analysis of stool BA profiles demonstrated clustering by recurrence status and post-treatment timepoint. Longitudinal faecal BA trajectories showed recovery of secondary BAs and their derivatives only in patients without recurrence. BSH activity increased over time only among non-relapsing patients (β = 0.056; likelihood ratio test p = 0.018). A joint longitudinal-survival model identified five stool BAs with area under the receiver operating characteristic curve >0.73 for predicting recurrence within 9 days post-CDI treatment.Conclusions:Gut BA metabolism dynamics differ in primary CDI patients between those developing recurrence and those who do not. Individual BAs show promise as potential novel biomarkers to predict CDI recurrence.

  • Journal article
    Grimes K, Beckwith EJ, Pearson WH, Jacobson J, Chaudhari S, Aughey GN, Larrouy-Maumus G, Southall TD, Dionne MSet al., 2022,

    A serine-folate metabolic unit controls resistance and tolerance of infection

    <jats:title>Abstract</jats:title><jats:p>Immune activation drives metabolic change in most animals. Immune-induced metabolic change is most conspicuous as a driver of pathology in serious or prolonged infection, but it is normally expected to be important to support immune function and recovery. Many of the signalling mechanisms linking immune detection with metabolic regulation, and their specific consequences, are unknown. Here, we show that<jats:italic>Drosophila melanogaster</jats:italic>respond to many bacterial infections by altering expression of genes of the folate cycle and associated enzymes of amino acid metabolism. The net result of these changes is increased flow of carbon from glycolysis into serine and glycine synthesis and a shift of folate cycle activity from the cytosol into the mitochondrion. Immune-induced transcriptional induction of<jats:italic>astray</jats:italic>and<jats:italic>Nmdmc</jats:italic>, the two most-induced of these enzymes, depends on<jats:italic>Dif</jats:italic>and<jats:italic>foxo</jats:italic>. Loss of<jats:italic>astray</jats:italic>or<jats:italic>Nmdmc</jats:italic>results in infection-specific immune defects. Our work thus shows a key mechanism that connects immune-induced changes in metabolic signalling with the serine-folate metabolic unit to result in changed immune function.</jats:p>

  • Journal article
    George PM, Reed A, Desai SR, Devaraj A, Faiez TS, Laverty S, Kanwal A, Esneau C, Liu MKC, Kamal F, Man WD-C, Kaul S, Singh S, Lamb G, Faizi FK, Schuliga M, Read J, Burgoyne T, Pinto AL, Micallef J, Bauwens E, Candiracci J, Bougoussa M, Herzog M, Raman L, Ahmetaj-Shala B, Turville S, Aggarwal A, Farne HA, Dalla Pria A, Aswani AD, Patella F, Borek WE, Mitchell JA, Bartlett NW, Dokal A, Xu X-N, Kelleher P, Shah A, Singanayagam Aet al., 2022,

    A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae.

    , Science Translational Medicine, Vol: 14, Pages: 1-16, ISSN: 1946-6234

    Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.

  • Journal article
    Shenker NS, Perdones-Montero A, Burke A, Stickland S, McDonald JAK, Cameron SJSet al., 2022,

    Human milk from tandem feeding dyads does not differ in metabolite and metataxonomic features when compared to single nursling dyads under six months of age

    , Metabolites, Vol: 12, ISSN: 2218-1989

    Given the long-term advantages of exclusive breastfeeding to infants and their mothers, there is both an individual and public health benefit to its promotion and support. Data on the composition of human milk over the course of a full period of lactation for a single nursling is sparse, but data on human milk composition during tandem feeding (feeding children of different ages from different pregnancies) is almost entirely absent. This leaves an important knowledge gap that potentially endangers the ability of parents to make a fully informed choice on infant feeding. We compared the metataxonomic and metabolite fingerprints of human milk samples from 15 tandem feeding dyads to that collected from ten exclusively breastfeeding single nursling dyads where the nursling is under six months of age. Uniquely, our cohort also included three tandem feeding nursling dyads where each child showed a preferential side for feeding—allowing a direct comparison between human milk compositions for different aged nurslings. Across our analysis of volume, total fat, estimation of total microbial load, metabolite fingerprinting, and metataxonomics, we showed no statistically significant differences between tandem feeding and single nursling dyads. This included comparisons of preferential side nurslings of different ages. Together, our findings support the practice of tandem feeding of nurslings, even when feeding an infant under six months.

  • Journal article
    Miguel-Romero L, Alqasmi M, Bacarizo J, Tan JA, Cogdell RJ, Chen J, Byron O, Christie GE, Marina A, Penades Jet al., 2022,

    Non-canonical Staphylococcus aureus pathogenicity island repression

    , Nucleic Acids Research, Vol: 50, Pages: 11109-11127, ISSN: 0305-1048

    Mobile genetic elements control their life cycles by the expression of a master repressor, whose function must be disabled to allow the spread of these elements in nature. Here we describe an unprecedented repression-derepression mechanism involved in the transfer of Staphylococcus aureus pathogenicity islands. Contrary to the classical phage and SaPI repressors, which are dimers, the SaPI1 repressor StlSaPI1 presents a unique tetramericconformation never seen before. Importantly, not just one but two tetramers are required for SaPI1 repression, which increases the novelty of the system. To derepress SaPI1, the phage-encoded protein Sri binds to and induces a conformational change in the DNA binding domains of StlSaPI1, preventing the binding of the repressor to its cognate StlSaPI1 sites. Finally, our findings demonstrate that this system is not exclusive to SaPI1 but widespread in nature. Overall, our results characterise a novel repression-induction system involved in the transfer of MGE-encoded virulence factors in nature.

  • Journal article
    Gonzalo X, Yrah S, Broda A, Laurenson I, Claxton P, Kostrzewa M, Drobniewski F, Larrouy-Maumus Get al., 2022,

    Performance of lipid fingerprint by routine matrix-assisted laser desorption/ionization time of flight for the diagnosis of Mycobacterium tuberculosis complex species

    , Clinical Microbiology and Infection, ISSN: 1198-743X

    Objectives:Rapid detection of bacterial pathogens to species and subspecies level is crucial for appropriate treatment, infection control and public health management. Currently, one of the challenges in clinical microbiology is the discrimination of mycobacterial sub-species within the M. tuberculosis complex (MTBC). Our objective was to evaluate the ability of a biosafe mycobacterial-lipid based approach to identify MTBC cultures and subspecies.Methods:A blinded study was performed using 90 mycobacterial clinical isolates strains comprising MTBC strains sub-cultured in Middlebrook 7H11 media supplemented with 10% OADC growth supplement and incubated for up to six weeks at 37°C and using the following 7 reference strains (M. tuberculosis H37Rv, M canettii, M. africanum, M. pinnipedii, M. caprae, M. bovis, M. bovis BCG) grown under the same conditions, in order to set the reference lipid database and test it against the 90 MTBC clinical isolates. Cultured mycobacteria were heat-inactivated and loaded onto the MALDI target followed by addition of the matrix. Acquisition of the data was done using the positive ion mode.Results:Based on the identification of clear and defined lipid signatures from the 7 reference strains, the method we have developed is fast (<10 mins) and produced interpretable profiles for all but four isolates, caused by poor ionization giving an n = 86 with interpretable spectra. The sensitivity and specificity of the MALDI-ToF, were 94.4 (95% CI 86.4-98.5) and 94.4 (95% CI 72.7-99.9) respectively. .Conclusions:Mycobacterial lipid profiling provides for a means of rapid, safe and accurate discrimination of species within the MTBC.

  • Conference paper
    Mullish BH, Paizs P, Alexander J, Verigos E, McDonald JAK, Ford L, Maneta-Stavrakaki S, Sani M, Roberts LA, Chrysostomou D, Kinross J, Monaghan T, Marchesi JR, Kao D, Takats Zet al., 2022,

    Intestinal microbiota transplant for recurrent Clostridioides difficile infection restores microbial arylsulfatases and sulfatide degradation: a novel mechanism of efficacy?

    , UEG Week 2022, Pages: 823-823
  • Journal article
    Thabet MA, Penadés JR, Haag AF, 2022,

    The ClpX protease is essential for removing the CI master repressor and completing prophage induction in <i>Staphylococcus aureus</i>

    <jats:title>Abstract</jats:title><jats:p>Bacteriophages (phages) are the predominant biological entities on the planet and play an important role in the spread of bacterial virulence, pathogenicity, and antimicrobial resistance. After infection, temperate phages can integrate in the bacterial chromosome thanks to the expression of the prophage-encoded CI master repressor. Upon SOS induction, and promoted by RecA*, CI auto-cleaves generating two fragments, one containing the N-terminal domain (NTD), which retains strong DNA-binding capacity, and other corresponding to the C-terminal part of the protein. However, it is unknown how the CI NTD is removed, a process that is essential to allow prophage induction. Here we identify for the first time that the specific interaction of the ClpX protease with the CI NTD repressor fragment is essential and sufficient for prophage activation after SOS-mediated CI autocleavage, defining the final stage in the prophage induction cascade. Our results provide unexpected roles for the bacterial protease ClpX in phage biology.</jats:p>

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