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Journal articleKrishna A, Liu B, Peacock SJ, et al., 2020,
The prevalence and implications of single-nucleotide polymorphisms in genes encoding 3 the RNA polymerase of clinical isolates of Staphylococcus aureus
, MicrobiologyOpen, Vol: 9, Pages: 1-8, ISSN: 2045-8827Central to the regulation of bacterial gene expression is the multisubunit enzyme RNA polymerase (RNAP), which is responsible for catalyzing transcription. As all adaptive processes are underpinned by changes in gene expression, the RNAP can be considered the major mediator of any adaptive response in the bacterial cell. In bacterial pathogens, theoretically, single nucleotide polymorphisms (SNPs) in genes that encode subunits of the RNAP and associated factors could mediate adaptation and confer a selective advantage to cope with biotic and abiotic stresses. We investigated this possibility by undertaking a systematic survey of SNPs in genes encoding the RNAP and associated factors in a collection of 1,429 methicillin‐resistant Staphylococcus aureus (MRSA) clinical isolates. We present evidence for the existence of several, hitherto unreported, nonsynonymous SNPs in genes encoding the RNAP and associated factors of MRSA ST22 clinical isolates and propose that the acquisition of amino acid substitutions in the RNAP could represent an adaptive strategy that contributes to the pathogenic success of MRSA.
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Journal articleAlix E, Godlee C, Cerny O, et al., 2020,
The tumor suppressor TMEM127 is a Nedd4-family E3 ligase adaptor required by Salmonella SteD to ubiquitinate and degrade MHC class II molecules
, Cell Host and Microbe, Vol: 28, Pages: 54-68.e7, ISSN: 1931-3128The Salmonella enterica effector SteD depletes mature MHC class II (mMHCII) molecules from the surface of infected antigen-presenting cells through ubiquitination of the cytoplasmic tail of the mMHCII β chain. Here, through a genome-wide mutant screen of human antigen-presenting cells, we show that the NEDD4 family HECT E3 ubiquitin ligase WWP2 and a tumor-suppressing transmembrane protein of unknown biochemical function, TMEM127, are required for SteD-dependent ubiquitination of mMHCII. Although evidently not involved in normal regulation of mMHCII, TMEM127 was essential for SteD to suppress both mMHCII antigen presentation in mouse dendritic cells and MHCII-dependent CD4+ T cell activation. We found that TMEM127 contains a canonical PPxY motif, which was required for binding to WWP2. SteD bound to TMEM127 and enabled TMEM127 to interact with and induce ubiquitination of mature MHCII. Furthermore, SteD also underwent TMEM127- and WWP2-dependent ubiquitination, which both contributed to its degradation and augmented its activity on mMHCII.
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Journal articleVincent C, Simoes da Silva C, Wadhawan A, et al., 2020,
Origins of metabolic pathology in Francisella-infected Drosophila
, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224The origins and causes of infection pathologies are often not understood. Despite this, the study of infection and immunity relies heavily on the ability to discern between potential sources of pathology. Work in the fruit fly has supported the assumption that mortality resulting from bacterial invasion is largely due to direct host-pathogen interactions, as lower pathogen loads are often associated with reduced pathology, and bacterial load upon death is predictable. However, the mechanisms through which these interactions bring about host death are complex. Here we show that infection with the bacterium Francisella novicida leads to metabolic dysregulation and, using treatment with a bacteriostatic antibiotic, we show that this pathology is the result of direct interaction between host and pathogen. We show that mutants of the immune deficiency immune pathway fail to exhibit similar metabolic dysregulation, supporting the idea that the reallocation of resources for immune-related activities contributes to metabolic dysregulation. Targeted investigation into the cross-talk between immune and metabolic pathways has the potential to illuminate some of this interaction.
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Journal articleWest K, Kanu C, Maric T, et al., 2020,
Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery
, Gut, Vol: 69, Pages: 1452-1459, ISSN: 0017-5749Due to the global increase in obesity rates and success of bariatric surgery in weight reduction, an increasing number of women now present pregnant with a previous bariatric procedure. This study investigates the extent of bariatric-associated metabolic and gut microbial alterations during pregnancy and their impact on fetal development.DesignA parallel metabonomic (1H NMR spectroscopy) and gut bacterial (16S rRNA gene amplicon sequencing) profiling approach was used to determine maternal longitudinal phenotypes associated with malabsorptive/mixed (n=25) or restrictive (n=16) procedures, compared to women with similar early pregnancy body mass index but without bariatric surgery (n=70). Metabolic profiles of offspring at birth were also analysed.ResultsPrevious malabsorptive, but not restrictive, procedures induced significant changes in maternal metabolic pathways involving branched-chain and aromatic amino acids with decreased circulation of leucine, isoleucine and isobutyrate, increased excretion of microbial-associated metabolites of protein putrefaction (phenylacetlyglutamine, p-cresol sulfate, indoxyl sulfate and p-hydroxyphenylacetate), and a shift in the gut microbiota. Urinary concentration of phenylacetylglutamine was significantly elevated in malabsorptive patients relative to controls (P=0.001) and was also elevated in urine of neonates born from these mothers (P=0.021). Furthermore, the maternal metabolic changes induced by malabsorptive surgery were associated with reduced maternal insulin resistance and fetal/birth weight.ConclusionMetabolism is altered in pregnant women with a previous malabsorptive bariatric surgery. These alterations may be beneficial for maternal outcomes, but the effect of elevated levels of phenolic and indolic compounds on fetal and infant health should be investigated further.
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Journal articleSlater S, Frankel G, 2020,
Advances and challenges in studying type III secretion effectors of attaching and effacing pathogens
, Frontiers in Cellular and Infection Microbiology, Vol: 10, Pages: 1-7, ISSN: 2235-2988 -
Journal articleSanchez-Garrido J, Shenoy A, 2020,
Regulation and repurposing of nutrient sensing and autophagy in innate immunity
, Autophagy, Vol: 17, Pages: 1571-1591, ISSN: 1554-8627Nutrients not only act as building blocks but also as signaling molecules. Nutrient-availability promotes cell growth and proliferation and suppresses catabolic processes, such as macroautophagy/autophagy. These effects are mediated by checkpoint kinases such as MTOR (mechanistic target of rapamycin kinase), which is activated by amino acids and growth factors, and AMP-activated protein kinase (AMPK), which is activated by low levels of glucose or ATP. These kinases have wide-ranging activities that can be co-opted by immune cells upon exposure to danger signals, cytokines or pathogens. Here, we discuss recent insight into the regulation and repurposing of nutrient-sensing responses by the innate immune system during infection. Moreover, we examine how natural mutations and pathogen-mediated interventions can alter the balance between anabolic and autophagic pathways leading to a breakdown in tissue homeostasis and/or host defense.
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Journal articleBroncel M, Dominicus C, Vigetti L, et al., 2020,
Profiling of myristoylation in <i>Toxoplasma</i> <i>gondii</i> reveals an <i>N</i>-myristoylated protein important for host cell penetration
, ELIFE, Vol: 9, ISSN: 2050-084X- Author Web Link
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- Citations: 12
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Journal articleWalter A, Unsleber S, Rismondo J, et al., 2020,
Phosphoglycerol-type wall and lipoteichoic acids are enantiomeric polymers differentiated by the stereospecific glycerophosphodiesterase GlpQ (vol 295, pg 4024, 2020)
, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 295, Pages: 8873-8873, ISSN: 0021-9258 -
Journal articleSchrader SM, Vaubourgeix J, Nathan C, 2020,
Biology of antimicrobial resistance and approaches to combat it
, SCIENCE TRANSLATIONAL MEDICINE, Vol: 12, ISSN: 1946-6234- Author Web Link
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- Citations: 73
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Journal articleSarah Wettstadt S, Lai E-M, Filloux AAM, 2020,
Solving the puzzle: connecting a heterologous Agrobacterium tumefaciens T6SS effector to a Pseudomonas aeruginosa spike complex
, Frontiers in Cellular and Infection Microbiology, Vol: 10, ISSN: 2235-2988The type VI secretion system (T6SS) is a contractile injection apparatus that translocates a spike loaded with various effectors directly into eukaryotic and prokaryotic target cells. Such T6SS spike consists of a needle-shaped trimer of VgrG proteins topped by a conical and sharp PAAR protein that facilitates puncturing of the target membrane. T6SS-delivered effector proteins can be either fused to one of the two spike proteins or interact with either in a highly specific manner. In Agrobacterium tumefaciens the T6SS effector Tde1 is targeted to its cognate VgrG1 protein. Here, we attempted to use a VgrG shuttle to deliver a heterologous T6SS effector by directing Tde1 onto a T6SS spike in Pseudomonas aeruginosa. For this, we designed chimeras between VgrG1 from A. tumefaciens and VgrG1a from P. aeruginosa and showed that modification of the spike protein hampered T6SS functionality in the presence of the Tde1 effector complex. We provide evidence suggesting that Tde1 specifically binds to the VgrG spike in the heterologous environment and propose that there are additional requirements to allow proper effector delivery and translocation. Our work sheds light on complex aspects of the molecular mechanisms of T6SS delivery and highlights some limitations on how effectors can be translocated using this nanomachine.
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