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Journal articleSumrall ET, Shen Y, Keller AP, et al., 2019,
Phage resistance at the cost of virulence: Listeria monocytogenes serovar 4b requires galactosylated teichoic acids for InlB-mediated invasion
, PLoS Pathogens, Vol: 15, ISSN: 1553-7366The intracellular pathogen Listeria monocytogenes is distinguished by its ability to invade and replicate within mammalian cells. Remarkably, of the 15 serovars within the genus, strains belonging to serovar 4b cause the majority of listeriosis clinical cases and outbreaks. The Listeria O-antigens are defined by subtle structural differences amongst the peptidoglycan-associated wall-teichoic acids (WTAs), and their specific glycosylation patterns. Here, we outline the genetic determinants required for WTA decoration in serovar 4b L. monocytogenes, and demonstrate the exact nature of the 4b-specific antigen. We show that challenge by bacteriophages selects for surviving clones that feature mutations in genes involved in teichoic acid glycosylation, leading to a loss of galactose from both wall teichoic acid and lipoteichoic acid molecules, and a switch from serovar 4b to 4d. Surprisingly, loss of this galactose decoration not only prevents phage adsorption, but leads to a complete loss of surface-associated Internalin B (InlB),the inability to form actin tails, and a virulence attenuation in vivo. We show that InlB specifically recognizes and attaches to galactosylated teichoic acid polymers, and is secreted upon loss of this modification, leading to a drastically reduced cellular invasiveness. Consequently, these phage-insensitive bacteria are unable to interact with cMet and gC1q-R host cell receptors, which normally trigger cellular uptake upon interaction with InlB. Collectively, we provide detailed mechanistic insight into the dual role of a surface antigen crucial for both phage adsorption and cellular invasiveness, demonstrating a trade-off between phage resistance and virulence in this opportunistic pathogen.
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Journal articleSinganayagam A, Snelgrove RJ, 2019,
Less burn, more fat: electronic cigarettes and pulmonary lipid homeostasis
, JOURNAL OF CLINICAL INVESTIGATION, Vol: 129, Pages: 4077-4079, ISSN: 0021-9738- Author Web Link
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- Citations: 4
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Conference paperSmith WD, Cameron SJ, Fletcher OL, et al., 2019,
PSEUDOMONAS AERUGINOSA METABOLOME DIFFERENCES BETWEEN CF AND NON-CF BRONCHIECTASIS DETECTED USING DIRECT-FROM-SAMPLE MASS SPECTROMETRY
, Pediatric Pulmonology, Publisher: WILEY, Pages: S313-S313, ISSN: 8755-6863 -
Journal articleWood TE, Howard SA, Forster A, et al., 2019,
The Pseudomonas aeruginosa T6SS delivers a periplasmic toxin that disrupts bacterial cell morphology
, Cell Reports, Vol: 29, Pages: 187-201.e7, ISSN: 2211-1247The type VI secretion system (T6SS) is crucialin interbacterial competition and is avirulence determinant ofmany Gram-negative bacteria. Several T6SS effectorsarecovalently fused to secreted T6SS structural components such asthe VgrG spike for delivery into target cells.In Pseudomonas aeruginosa, theVgrG2b effector waspreviously proposedto mediatebacterial internalisation into eukaryotic cells. In this work, wefind that the VgrG2b C-terminal domain(VgrG2bC-ter) elicits toxicity in the bacterial periplasm, counteracted by a cognate immunity protein.We resolve thestructure of VgrG2bC-ter and confirm it is a member ofthezinc-metallopeptidasefamily of enzymes. We show that this effector causesmembrane blebbing atmidcell, whichsuggests a distincttype of T6SS-mediated growthinhibition through interference with cell division, mimicking the impact of β-lactam antibiotics. Ourstudyintroduces a further effector family to the T6SS arsenaland demonstrates that VgrG2b can target both prokaryotic and eukaryotic cells.
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Journal articleCain AK, Nolan LM, Sullivan GJ, et al., 2019,
Complete genome sequence of pseudomonas aeruginosa reference strain PAK
, Microbiology Resource Announcements, Vol: 8, ISSN: 2576-098XWe report the complete genome of Pseudomonas aeruginosa strain PAK, a strain which has been instrumental in the study of a range of P. aeruginosa virulence and pathogenesis factors and has been used for over 50 years as a laboratory reference strain.
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Journal articleRudramurthy SM, Colley T, Abdolrasouli A, et al., 2019,
In vitro antifungal activity of a novel topical triazole PC945 against emerging yeast Candida auris
, Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 2943-2949, ISSN: 0305-7453ObjectivesManagement of Candida auris infection is difficult as this yeast exhibits resistance to different classes of antifungals, necessitating the development of new antifungals. The aim of this study was to investigate the susceptibility of C. auris to a novel antifungal triazole, PC945, optimized for topical delivery.MethodsA collection of 50 clinical isolates was obtained from a tertiary care hospital in North India. Nine isolates from the UK, 10 from a CDC panel (USA) and 3 from the CBS-KNAW culture collection (Japanese and South Korean isolates) were also obtained. MICs (azole endpoint) of PC945 and other triazoles were determined in accordance with CLSI M27 (third edition). Quality control strains were included [Candida parapsilosis (ATCC 22019) and Candida krusei (ATCC 6258)].ResultsSeventy-four percent of isolates tested showed reduced susceptibility to fluconazole (≥64 mg/L). PC945 (geometric mean MIC = 0.058 mg/L) was 7.4-fold and 1.5-fold more potent than voriconazole and posaconazole, respectively (both P < 0.01). PC945 MIC values correlated with those of voriconazole or posaconazole, and only three isolates were found to be cross-resistant between PC945 and other azoles. ERG11 sequence analysis revealed several mutations, but no correlation could be established with the MIC of PC945. Tentative epidemiological cut-off values (ECOFFs) evaluated by CLSI’s ECOFF Finder (at 99%) with 24 h reading of MICs were 1, 4 and 1 mg/L for PC945, voriconazole and posaconazole, respectively. MIC values for quality control strains of all triazoles were in the normal ranges.ConclusionsPC945 was found to be a more potent inhibitor than posaconazole, voriconazole and fluconazole of C. auris isolates collected globally, warranting further laboratory and clinical evaluations.
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Journal articleMullish BH, McDonald JAK, Pechlivanis A, et al., 2019,
Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent <i>Clostridioides difficile</i> infection
, Gut, Vol: 68, Pages: 1791-1800, ISSN: 0017-5749<jats:sec><jats:title>Objective</jats:title><jats:p>Faecal microbiota transplant (FMT) effectively treats recurrent <jats:italic>Clostridioides difficile</jats:italic> infection (rCDI), but its mechanisms of action remain poorly defined. Certain bile acids affect <jats:italic>C. difficile</jats:italic> germination or vegetative growth. We hypothesised that loss of gut microbiota-derived bile salt hydrolases (BSHs) predisposes to CDI by perturbing gut bile metabolism, and that BSH restitution is a key mediator of FMT’s efficacy in treating the condition.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Using stool collected from patients and donors pre-FMT/post-FMT for rCDI, we performed 16S rRNA gene sequencing, ultra performance liquid chromatography mass spectrometry (UPLC-MS) bile acid profiling, BSH activity measurement, and qPCR of <jats:italic>bsh</jats:italic>/<jats:italic>bai</jats:italic>CD genes involved in bile metabolism. Human data were validated in <jats:italic>C. difficile</jats:italic> batch cultures and a C57BL/6 mouse model of rCDI.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>From metataxonomics, pre-FMT stool demonstrated a reduced proportion of BSH-producing bacterial species compared with donors/post-FMT. Pre-FMT stool was enriched in taurocholic acid (TCA, a potent <jats:italic>C. difficile</jats:italic> germinant); TCA levels negatively correlated with key bacterial genera containing BSH-producing organisms. Post-FMT samples demonstrated recovered BSH activity and <jats:italic>bsh</jats:italic>/<jats:italic>bai</jats:italic>CD gene copy number compared with pretreatment (p<0.05). In batch cultures, supernatant from engineered <jats:italic>bsh</jats:italic>-expressing <jats:italic>E
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Journal articleAllegretti JR, Mullish B, Nativ L, et al., 2019,
185 Evaluating Dynamics of Bile Acid Metabolism to Predict Recurrence of Clostridioides difficile Infection
, American Journal of Gastroenterology, Vol: 114, Pages: S113-S113, ISSN: 0002-9270<jats:sec> <jats:title>INTRODUCTION:</jats:title> <jats:p>Recurrent <jats:italic toggle="yes">Clostridioides difficile</jats:italic> infection (CDI) is a major public health problem. The ability of commensal gut microbiota to metabolize primary into secondary bile acids plays a role in protection against this infection. Current clinical prediction tools for CDI recurrence do not incorporate biomarkers predictive of protective microbiota functionalities. We investigated metabolomic predictors of <jats:italic toggle="yes">C. difficile</jats:italic> recurrence.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>We conducted a prospective longitudinal study of patients experiencing a first CDI episode. Patients testing positive with either enzyme immunoassay (EIA) toxin or polymerase chain reaction (PCR), and being treated for CDI, were eligible for inclusion. Serial stool samples were collected at diagnosis through week-8 post-completion of anti-CDI therapy if no recurrence, or until the point of recurrence (defined as diarrhea with positive <jats:italic toggle="yes">C</jats:italic>. <jats:italic toggle="yes">difficile</jats:italic> EIA toxin stool test). Liquid chromatography-mass spectrometry was performed to profile fecal bile acids. The week 1 post-antibiotic time point was chosen to assess for potential predictors. We derived a univariate logistic regression model predicting recurrence and computed the AUC (c-statistic) on discriminatory ability. The Youden index was calculated as the value that maximizes sensitivity and specificity.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>29 first episode CDI patients were enrolled. 10 patient
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Journal articleAllegretti JR, Mullish B, Hurtado J, et al., 2019,
837 Short Chain Fatty Acid Profiles Are Altered by Fecal Microbiota Transplantation for the Treatment of Inflammatory Bowel Disease and Recurrent Clostridioides difficile Infection
, American Journal of Gastroenterology, Vol: 114, Pages: S484-S485, ISSN: 0002-9270<jats:sec> <jats:title>INTRODUCTION:</jats:title> <jats:p>Recurrent <jats:italic toggle="yes">C. difficile</jats:italic> infection (rCDI) is a major challenge among patients with inflammatory bowel disease (IBD). Perturbation of microbiota-mediated metabolism of short chain fatty acids (SCFA) has been reported in IBD patients. Fecal microbiota transplantation (FMT), an established therapy for rCDI, alters gut microbiota composition, but effects on SCFA are unclear. Accordingly, this study assessed SCFA profiles in IBD patients with rCDI pre- and post-FMT.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>This open-label, prospective, single-arm multi-center cohort study enrolled patients from 4 tertiary care centers. Patients with IBD and ≥2 episodes of CDI received a single colonoscopic FMT from a universal stool bank. The primary outcome was CDI recurrence up to week 8 defined as diarrhea and EIA-positive toxin testing for <jats:italic toggle="yes">C. difficile</jats:italic>. Stool for metabolomic profiling was collected pre-FMT and week 1, 8 and 12 weeks post-FMT. A targeted gas chromatography-mass spectrometry protocol was used for the identification and quantification of SCFA. SCFA concentrations were analyzed via univariate analysis, comparing groups (e.g. pre- <jats:italic toggle="yes">vs</jats:italic> post-FMT).</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>37 participants were enrolled, with mean age of 37.6 years (range 20-76) and primarily female (n = 21, 57%). 14 had Crohn’s disease (CD) (mean HBI = 6.4) and 23 had ulcerative colitis (UC) (mean Partial Mayo Score = 4.5). Mean baseline fecal calprotectin was 1804.8 +/- 2307.7 Overall, 3
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Journal articleBudden KF, Shukla SD, Rehman SF, et al., 2019,
Functional effects of the microbiota in chronic respiratory disease
, Lancet Respiratory Medicine, Vol: 7, Pages: 907-920, ISSN: 2213-2600The composition of the lung microbiome is increasingly well characterised, with changes in microbial diversity or abundance observed in association with several chronic respiratory diseases such as asthma, cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease. However, the precise effects of the microbiome on pulmonary health and the functional mechanisms by which it regulates host immunity are only now beginning to be elucidated. Bacteria, viruses, and fungi from both the upper and lower respiratory tract produce structural ligands and metabolites that interact with the host and alter the development and progression of chronic respiratory diseases. Here, we review recent advances in our understanding of the composition of the lung microbiome, including the virome and mycobiome, the mechanisms by which these microbes interact with host immunity, and their functional effects on the pathogenesis, exacerbations, and comorbidities of chronic respiratory diseases. We also describe the present understanding of how respiratory microbiota can influence the efficacy of common therapies for chronic respiratory disease, and the potential of manipulation of the microbiome as a therapeutic strategy. Finally, we highlight some of the limitations in the field and propose how these could be addressed in future research.
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