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Journal articleZeden MS, Kviatkovski I, Schuster CF, et al., 2019,
Identification of the main glutamine and glutamate transporters in<i>Staphylococcus aureus</i>and their impact on c-di-AMP production
<jats:title>Summary</jats:title><jats:p>A<jats:italic>Staphylococcus aureus</jats:italic>strain deleted for the c-di-AMP cyclase gene<jats:italic>dacA</jats:italic>is unable to survive in rich medium unless it acquires compensatory mutations. Previously identified mutations were in<jats:italic>opuD</jats:italic>, encoding the main glycine-betaine transporter, and<jats:italic>alsT</jats:italic>, encoding a predicted amino acid transporter. Here, we show that inactivation of OpuD restores the cell size of a<jats:italic>dacA</jats:italic>mutant to near wild-type size, while inactivation of AlsT does not, suggesting two different mechanisms for the growth rescue. AlsT was identified as an efficient glutamine transporter, indicating that preventing glutamine uptake in rich medium rescues the growth of the<jats:italic>S. aureus dacA</jats:italic>mutant. In addition, GltS was identified as a glutamine transporter. By performing growth curves with WT,<jats:italic>alsT</jats:italic>and<jats:italic>gltS</jats:italic>mutant strains in defined medium supplemented with ammonium, glutamine or glutamate, we revealed that ammonium and glutamine, but not glutamate promote the growth of<jats:italic>S. aureus</jats:italic>. This suggests that besides ammonium also glutamine can serve as a nitrogen source under these conditions. Ammonium and uptake of glutamine via AlsT inhibited c-di-AMP production, while glutamate uptake had no effect. These findings provide, besides the previously reported link between potassium and osmolyte uptake, a connection between nitrogen metabolism and c-di-AMP signalling in<jats:italic>S. aureus</jats:italic>.</jats:p><jats:sec><jats:title>Graphical abstract</jats:title><jats:fig id="ufig1" position="float" fig-type="figure" orientation="portrait"><j
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Journal articleSinganayagam A, Glanville N, Cuthbertson L, et al., 2019,
Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease
, Science Translational Medicine, Vol: 11, Pages: 1-13, ISSN: 1946-6234Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp-/-) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.
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Journal articleRonneau S, Helaine S, 2019,
Clarifying the Link between Toxin-Antitoxin Modules and Bacterial Persistence
, JOURNAL OF MOLECULAR BIOLOGY, Vol: 431, Pages: 3462-3471, ISSN: 0022-2836- Author Web Link
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Journal articleFuqua C, Filloux A, Ghigo J-M, et al., 2019,
Biofilms 2018: a diversity of microbes and mechanisms
, Journal of Bacteriology, Vol: 201, Pages: e00118-e00119, ISSN: 0021-9193The 8th ASM Conference on Biofilms was held in Washington D.C. on October 7-11, 2018. This very highly subscribed meeting represented a wide breadth of current research in biofilms, and included over 500 attendees, 12 sessions with 64 oral presentations, and four poster sessions with about 400 posters.
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Journal articleCiges-Tomas JR, Alite C, Humphrey S, et al., 2019,
The structure of a polygamous repressor reveals how phage-inducible chromosomal islands spread in nature
, Nature Communications, Vol: 10, ISSN: 2041-1723Stl is a master repressor encoded by Staphylococcus aureus pathogenicity islands (SaPIs) that maintains integration of these elements in the bacterial chromosome. After infection or induction of a resident helper phage, SaPIs are de-repressed by specific interactions of phage proteins with Stl. SaPIs have evolved a fascinating mechanism to ensure their promiscuous transfer by targeting structurally unrelated proteins performing identically conserved functions for the phage. Here we decipher the molecular mechanism of this elegant strategy by determining the structure of SaPIbov1 Stl alone and in complex with two structurally unrelated dUTPases from different S. aureus phages. Remarkably, SaPIbov1 Stl has evolved different domains implicated in DNA and partner recognition specificity. This work presents the solved structure of a SaPI repressor protein and the discovery of a modular repressor that acquires multispecificity through domain recruiting. Our results establish the mechanism that allows widespread dissemination of SaPIs in nature.
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Journal articleRismondo J, Halbedel S, Grundling A, 2019,
Cell shape and antibiotic resistance is maintained by the activity of multiple FtsW and RodA enzymes in Listeria monocytogenes
, mBio, Vol: 10, Pages: 1-17, ISSN: 2150-7511Rod-shaped bacteria have two modes of peptidoglycan synthesis: lateral synthesis and synthesis at the cell division site. These two processes are controlled by two macromolecular protein complexes, the elongasome and divisome. Recently, it has been shown that the Bacillus subtilis RodA protein, which forms part of the elongasome, has peptidoglycan glycosyltransferase activity. The cell division specific RodA homolog FtsW fulfils a similar role at the divisome. The human pathogen Listeria monocytogenes encodes up to six FtsW/RodA homologs, however their functions have not yet been investigated. Analysis of deletion and depletion strains led to the identification of the essential cell division-specific FtsW protein, FtsW1. Interestingly, L. monocytogenes encodes a second FtsW protein, FtsW2, which can compensate for the lack of FtsW1, when expressed from an inducible promoter. L. monocytogenes also possesses three RodA homologs, RodA1, RodA2 and RodA3 and their combined absence is lethal. Cells of a rodA1/rodA3 double mutant are shorter and have increased antibiotic and lysozyme sensitivity, probably due to a weakened cell wall. Results from promoter activity assays revealed that expression of rodA3 and ftsW2 is induced in the presence of antibiotics targeting penicillin binding proteins. Consistent with this, a rodA3 mutant was more susceptible to the β-lactam antibiotic cefuroxime. Interestingly, overexpression of RodA3 also led to increased cefuroxime sensitivity. Our study highlights that L. monocytogenes encodes a multitude of functional FtsW and RodA enzymes to produce its rigid cell wall and that their expression needs to be tightly regulated to maintain growth, cell division and antibiotic resistance.
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Journal articleWood TE, Howard SA, Wettstadt S, et al., 2019,
PAAR proteins act as the ‘sorting hat’ of the type VI secretion system
, Microbiology, Vol: 165, Pages: 1203-1218, ISSN: 1350-0872Bacteria exist in polymicrobial environments and compete to prevail in a niche. The type VI secretion system (T6SS) is a nanomachine employed by Gram-negative bacteria to deliver effector proteins into target cells. Consequently, T6SS-positive bacteria produce a wealth of antibacterial effector proteins to promote their survival among a prokaryotic community. These toxins are loaded onto the VgrG–PAAR spike and Hcp tube of the T6SS apparatus and recent work has started to document the specificity of effectors for certain spike components. Pseudomonas aeruginosa encodes several PAAR proteins, whose roles have been poorly investigated. Here we describe a phospholipase family antibacterial effector immunity pair from Pseudomonas aeruginosa and demonstrate that a specific PAAR protein is necessary for the delivery of the effector and its cognate VgrG. Furthermore, the PAAR protein appears to restrict the delivery of other phospholipase effectors that utilise distinct VgrG proteins. We provide further evidence for competition for PAAR protein recruitment to the T6SS apparatus, which determines the identities of the delivered effectors.
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Journal articleChiang YN, Penades JR, Chen J, 2019,
Genetic transduction by phages and chromosomal islands: The new and noncanonical
, PLoS Pathogens, Vol: 15, Pages: 1-7, ISSN: 1553-7366 -
Journal articleMcIlvride S, Nikolova V, Fan HM, et al., 2019,
Obeticholic acid ameliorates dyslipidemia but not glucose tolerance in mouse model of gestational diabetes.
, Am J Physiol Endocrinol Metab, Vol: 317, Pages: E399-E410Metabolism alters markedly with advancing gestation, characterized by progressive insulin resistance, dyslipidemia, and raised serum bile acids. The nuclear receptor farnesoid X receptor (FXR) has an integral role in bile acid homeostasis and modulates glucose and lipid metabolism. FXR is known to be functionally suppressed in pregnancy. The FXR agonist, obeticholic acid (OCA), improves insulin sensitivity in patients with type 2 diabetes with nonalcoholic fatty liver disease. We therefore hypothesized that OCA treatment during pregnancy could improve disease severity in a mouse model of gestational diabetes mellitus (GDM). C57BL/6J mice were fed a high-fat diet (HFD; 60% kcal from fat) for 4 wk before and throughout pregnancy to induce GDM. The impact of the diet supplemented with 0.03% OCA throughout pregnancy was studied. Pregnant HFD-fed mice displayed insulin resistance and dyslipidemia. OCA significantly reduced plasma cholesterol concentrations in nonpregnant and pregnant HFD-fed mice (by 22.4%, P < 0.05 and 36.4%, P < 0.001, respectively) and reduced the impact of pregnancy on insulin resistance but did not change glucose tolerance. In nonpregnant HFD-fed mice, OCA ameliorated weight gain, reduced mRNA expression of inflammatory markers in white adipose tissue, and reduced plasma glucagon-like peptide 1 concentrations (by 62.7%, P < 0.01). However, these effects were not evident in pregnant mice. OCA administration can normalize plasma cholesterol levels in a mouse model of GDM. However, the absence of several of the effects of OCA in pregnant mice indicates that the agonistic action of OCA is not sufficient to overcome many metabolic consequences of the pregnancy-associated reduction in FXR activity.
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Conference paperRiaz Z, Wright M, Atkinson S, et al., 2019,
Malignant and cirrhotic ascites demonstrate a similar microbiome profile
, British Association for the Study of the Liver (BASL) Annual Meeting
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