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• Journal article
  Vakili M, Aliyali M, Mortezaee V, Mahdaviani SA, Poorabdollah M, Mirenayat MS, Fakharian A, Hassanzad M, Abastabar M, Charati JY, Haghani I, Tavakoli M, Maleki M, Armstrong-James D, Hedayati MTet al., 2020,

  Relationship between spirometry results and colonisation of <i>Aspergillus</i> species in allergic asthma

  , CLINICAL RESPIRATORY JOURNAL, Vol: 14, Pages: 748-757, ISSN: 1752-6981
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• Journal article
  Ding NS, McDonald JAK, Perdones-Montero A, Rees DN, Adegbola SO, Misra R, Hendy P, Penez L, Marchesi JR, Holmes E, Sarafian MH, Hart ALet al., 2020,

  Metabonomics and the Gut Microbiome Associated With Primary Response to Anti-TNF Therapy in Crohn's Disease

  , JOURNAL OF CROHNS & COLITIS, Vol: 14, Pages: 1090-1102, ISSN: 1873-9946
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  • Citations: 51
• Journal article
  Pataia V, McIlvride S, Papacleovoulou G, Ovadia C, McDonald JAK, Wahlstrom A, Jansen E, Adorini L, Shapiro D, Marchesi JR, Marschall H-U, Williamson Cet al., 2020,

  Obeticholic acid improves fetal bile acid profile in a mouse model of gestational hypercholanemia

  , AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, Vol: 319, Pages: G197-G211, ISSN: 0193-1857
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  • Citations: 5
• Journal article
  Murphy P, Xu Y, Rouse SL, Jaffray EG, Plechanovova A, Matthews SJ, Carlos Penedo J, Hay RTet al., 2020,

  Functional 3D architecture in an intrinsically disordered E3 ligase domain facilitates ubiquitin transfer

  , NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
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  • Citations: 7
• Journal article
  Currie AJ, Main ET, Wilson HM, Armstrong-James D, Warris Aet al., 2020,

  CFTR Modulators Dampen<i>Aspergillus</i>-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes

  , FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, Vol: 10, ISSN: 2235-2988
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  • Citations: 10
• Journal article
  Yi L, Rebollo-Ramirez S, Larrouy-Maumus G, 2020,

  Metabolomics reveals that the cAMP receptor protein regulates nitrogen and peptidoglycan synthesis in Mycobacterium tuberculosis

  , RSC Advances: an international journal to further the chemical sciences, Vol: 10, Pages: 26212-26219, ISSN: 2046-2069

  Mycobacterium tuberculosis requires extensive sensing and response to environment for its successful survival and pathogenesis, and signalling by cyclic adenosine 3′,5′-monophosphate (cAMP) is an important mechanism. cAMP regulates expression of target genes via interaction with downstream proteins, one of which is cAMP receptor protein (CRP), a global transcriptional regulator. Previous genomic works had identified regulon of CRP and investigated transcriptional changes in crp deletion mutant, however a link to downstream metabolomic events were lacking, which would help better understand roles of CRP. This work aims at investigating changes at metabolome level in M. tuberculosis crp deletion mutant combining untargeted LC-MS analysis and 13C isotope tracing analysis. The results were compared with previously published RNA sequencing data. We identified increasing abundances of metabolites related to nitrogen metabolism including ornithine, citrulline and glutamate derivatives, while 13C isotope labelling analysis further showed changes in turnover of these metabolites and amino acids, suggesting regulatory roles of CRP in nitrogen metabolism. Upregulation of diaminopimelic acid and its related genes also suggested role of CRP in regulation of peptidoglycan synthesis. This study provides insights on metabolomic aspects of cAMP-CRP regulatory pathway in M. tuberculosis and links to previously published transcriptomic data drawing a more complete map.

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• Journal article
  Krishna A, Liu B, Peacock SJ, Wigneshweraraj Set 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: 2045-8827

  Central 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 article
  Alix E, Godlee C, Cerny O, Blundell S, Tocci R, Liu M, Pruneda JN, Swatek KN, Komander D, Sleap T, Holden Det 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: 1931-3128

  The 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 article
  Vincent C, Simoes da Silva C, Wadhawan A, Dionne Met al., 2020,

  Origins of metabolic pathology in Francisella-infected Drosophila

  , Frontiers in Immunology, Vol: 11, ISSN: 1664-3224

  The 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 article
  West K, Kanu C, Maric T, McDonald J, Nicholson J, Li J, Johnson M, Holmes E, Savvidou Met al., 2020,

  Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery

  , Gut, Vol: 69, Pages: 1452-1459, ISSN: 0017-5749

  Due 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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