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Journal articleFarne H, Singanayagam A, 2021,
Gateway to the lungs: Viral entry receptors and susceptibility to COVID-19
, RESPIROLOGY, Vol: 26, Pages: 404-405, ISSN: 1323-7799 -
Journal articleBorah K, Mendum TA, Hawkins ND, et al., 2021,
Metabolic fluxes for nutritional flexibility of <i>Mycobacterium tuberculosis</i>
, MOLECULAR SYSTEMS BIOLOGY, Vol: 17, ISSN: 1744-4292- Author Web Link
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- Citations: 11
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Journal articleBreyer F, Hartlova A, Thurston T, et al., 2021,
TPL-2 kinase induces phagosome acidification to promote macrophage killing of bacteria
, The EMBO Journal, Vol: 40, Pages: 1-19, ISSN: 0261-4189Tumour progression locus 2 (TPL-2) kinase mediates Toll-like receptor (TLR) activation of ERK1/2 and p38α MAP kinases in myeloid cells to modulate expression of key cytokines in innate immunity. This study identified a novel MAP kinase-independent regulatory function for TPL-2 in phagosome maturation, an essential process for killing of phagocytosed microbes. TPL-2 catalytic activity was demonstrated to induce phagosome acidification and proteolysis in primary mouse and human macrophages following uptake of latex beads. Quantitative proteomics revealed that blocking TPL-2 catalytic activity significantly altered the protein composition of phagosomes, particularly reducing the abundance of V-ATPase proton pump subunits. Furthermore, TPL-2 stimulated the phosphorylation of DMXL1, a regulator of V-ATPases, to induce V-ATPase assembly and phagosome acidification. Consistent with these results, TPL-2 catalytic activity was required for phagosome acidification and the efficient killing of Staphylococcus aureus and Citrobacter rodentium following phagocytic uptake by macrophages. TPL-2 therefore controls innate immune responses of macrophages to bacteria via V-ATPase induction of phagosome maturation.
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Journal articleMcQuail J, Carpousis AJ, Wigneshweraraj S, 2021,
The association between Hfq and RNase E in long-term nitrogen starved<i>Escherichia coli</i>
<jats:title>Abstract</jats:title><jats:p>Under conditions of nutrient adversity, bacteria adjust metabolism to minimise cellular energy usage. This is often achieved by controlling the synthesis and degradation of RNA. In<jats:italic>Escherichia coli</jats:italic>, RNase E is the central enzyme involved in RNA degradation and serves as a scaffold for the assembly of the multiprotein complex known as the RNA degradosome. The activity of RNase E against specific mRNAs can also be regulated by the action of small RNAs (sRNA). In this case, the ubiquitous bacterial chaperone Hfq bound to sRNAs can interact with the RNA degradosome for the sRNA guided degradation of target RNAs. The RNA degradosome and Hfq have never been visualised together in live bacteria. We now show that in long-term nitrogen starved<jats:italic>E. coli</jats:italic>, both RNase E and Hfq co-localise in a single, large focus. This subcellular assembly, which we refer to as the H-body, forms by a liquid-liquid phase separation type mechanism and includes components of the RNA degradosome, namely, the helicase RhlB and the exoribonuclease polynucleotide phosphorylase. The results support the existence of an hitherto unreported subcellular compartmentalisation of a process(s) associated with RNA management in stressed bacteria.</jats:p>
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Journal articleGhani R, Mullish BH, McDonald JAK, et al., 2021,
Disease prevention not decolonization – a model for fecal microbiota transplantation in patients colonized with multidrug-resistant organisms
, Clinical Infectious Diseases, Vol: 72, Pages: 1444-1447, ISSN: 1058-4838Fecal microbiota transplantation (FMT) yields variable intestinal decolonization results for multidrug-resistant organisms (MDROs). This study showed significant reductions in antibiotic duration, bacteremia and length of stay in 20 patients colonized/ infected with MDRO receiving FMT (compared to pre-FMT history, and a matched group not receiving FMT), despite modest decolonization rates.
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Journal articleSabnis A, Haggard K, Kloeckner A, et al., 2021,
Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane
, eLife, Vol: 10, Pages: 1-26, ISSN: 2050-084XColistin is an antibiotic of last resort, but has poor efficacy and resistance is a growing problem. Whilst it is well established that colistin disrupts the bacterial outer membrane (OM) by selectively targeting lipopolysaccharide (LPS), it was unclear how this led to bacterial killing. We discovered that MCR-1 mediated colistin resistance in Escherichia coli is due to modified LPS at the cytoplasmic rather than OM. In doing so, we also demonstrated that colistin exerts bactericidal activity by targeting LPS in the cytoplasmic membrane (CM). We then exploited this information to devise a new therapeutic approach. Using the LPS transport inhibitor murepavadin, we were able to cause LPS accumulation in the CM of Pseudomonas aeruginosa, which resulted in increased susceptibility to colistin in vitro and improved treatment efficacy in vivo. These findings reveal new insight into the mechanism by which colistin kills bacteria, providing the foundations for novel approaches to enhance therapeutic outcomes.
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Journal articleZaveri A, Bose A, Sharma S, et al., 2021,
Mycobacterial STAND adenylyl cyclases: the HTH domain binds DNA to form biocrystallized nucleoids
, Biophysical Journal, Vol: 120, Pages: 1231-1246, ISSN: 0006-3495Mycobacteria harbor a unique class of adenylyl cyclases with a complex domain organization consisting of an N-terminal putative adenylyl cyclase domain fused to a nucleotide-binding adaptor shared by apoptotic protease-activating factor-1, plant resistance proteins, and CED-4 (NB-ARC) domain, a tetratricopeptide repeat (TPR) domain, and a C-terminal helix-turn-helix (HTH) domain. The products of the rv0891c-rv0890c genes represent a split gene pair, where Rv0891c has sequence similarity to adenylyl cyclases, and Rv0890c harbors the NB-ARC-TPR-HTH domains. Rv0891c had very low adenylyl cyclase activity so it could represent a pseudoenzyme. By analyzing the genomic locus, we could express and purify Rv0890c and find that the NB-ARC domain binds ATP and ADP, but does not hydrolyze these nucleotides. Using systematic evolution of ligands by exponential enrichment (SELEX), we identified DNA sequences that bound to the HTH domain of Rv0890c. Uniquely, the HTH domain could also bind RNA. Atomic force microscopy revealed that binding of Rv0890c to DNA was sequence independent, and binding of adenine nucleotides to the protein induced the formation of higher order structures that may represent biocrystalline nucleoids. This represents the first characterization of this group of proteins and their unusual biochemical properties warrant further studies into their physiological roles in future.
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Journal articlevan Sorge NM, Bonsor DA, Deng L, et al., 2021,
Bacterial protein domains with a novel Ig-like fold target human CEACAM receptors
, The EMBO Journal, Vol: 40, Pages: 1-20, ISSN: 0261-4189Streptococcus agalactiae, also known as group B Streptococcus (GBS), is the major cause of neonatal sepsis in humans. A critical step to infection is adhesion of bacteria to epithelial surfaces. GBS adhesins have been identified to bind extracellular matrix components and cellular receptors. However, several putative adhesins have no host binding partner characterised. We report here that surface-expressed β protein of GBS binds to human CEACAM1 and CEACAM5 receptors. A crystal structure of the complex showed that an IgSF domain in β represents a novel Ig-fold subtype called IgI3, in which unique features allow binding to CEACAM1. Bioinformatic assessment revealed that this newly identified IgI3 fold is not exclusively present in GBS but is predicted to be present in adhesins from other clinically important human pathogens. In agreement with this prediction, we found that CEACAM1 binds to an IgI3 domain found in an adhesin from a different streptococcal species. Overall, our results indicate that the IgI3 fold could provide a broadly applied mechanism for bacteria to target CEACAMs.
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Journal articleStephens J, Wong J, Broomhead R, et al., 2021,
Raised serum amylase in patients with COVID-19 may not be associated with pancreatitis
, British Journal of Surgery, Vol: 108, Pages: 152-153, ISSN: 0007-1323 -
Journal articleRismondo J, Gillis A, Grundling A, 2021,
Modifications of cell wall polymers in Gram-positive bacteria by multi-component transmembrane glycosylation systems
, Current Opinion in Microbiology, Vol: 60, Pages: 24-33, ISSN: 1369-5274Secondary cell wall polymers fulfil diverse and important functions within the cell wall of Gram-positive bacteria. Here, we will provide a brief overview of the principles of teichoic acid and complex secondary cell wall polysaccharide biosynthesis pathways in Firmicutes and summarize the recently revised mechanism for the decoration of teichoic acids with d-alanines. Many cell wall polymers are decorated with glycosyl groups, either intracellularly or extracellularly. The main focus of this review will be on the extracellular glycosylation mechanism and recent advances that have been made in the identification of enzymes involved in this process. Based on the proteins involved, we propose to rename the system to multi-component transmembrane glycosylation system in place of three-component glycosylation system.
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