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Journal articleKierdorf K, Hersperger F, Sharrock J, et al., 2020,
Muscle function and homeostasis require cytokine inhibition of AKT activity in Drosophila
, eLife, Vol: 9, ISSN: 2050-084XUnpaired ligands are secreted signals that act via a GP130-like receptor, domeless, to activate JAK/STAT signalling in Drosophila. Like many mammalian cytokines, unpaireds can be activated by infection and other stresses and can promote insulin resistance in target tissues. However, the importance of this effect in non-inflammatory physiology is unknown. Here, we identify a requirement for unpaired-JAK signalling as a metabolic regulator in healthy adult Drosophila muscle. Adult muscles show basal JAK-STAT signalling activity in the absence of any immune challenge. Plasmatocytes (Drosophila macrophages) are an important source of this tonic signal. Loss of the dome receptor on adult muscles significantly reduces lifespan and causes local and systemic metabolic pathology. These pathologies result from hyperactivation of AKT and consequent deregulation of metabolism. Thus, we identify a cytokine signal that must be received in muscle to control AKT activity and metabolic homeostasis.
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Journal articleFillol-Salom A, Miguel-Romero L, Marina A, et al., 2020,
Beyond the CRISPR-Cas safeguard: PICI-encoded innate immune systems protect bacteria from bacteriophage predation
, CURRENT OPINION IN MICROBIOLOGY, Vol: 56, Pages: 52-58, ISSN: 1369-5274- Author Web Link
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- Citations: 14
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Conference paperGhani R, Mullish BH, McDonald J, et al., 2020,
Disease prevention not decolonisation: a cohort study for faecal microbiota transplantation for patients colonised with multidrug-resistant organisms
, ECCMID 2020 -
Journal articleHamilton C, Larrouy-Maumus G, Anand P, 2020,
Phosphatidylinositol Acyl Chains Configure TLR-Dependent Priming and Activation of the NLRP3 Inflammasome
, BioRxiv 2020Abstract Lipids are important in establishing cellular homeostasis by conducting varied functions including relay of extracellular signals. Imbalance in lipid homeostasis results in metabolic diseases, and is tightly connected to discrepancies in immune signalling. The phosphorylation status of the lipid second messenger phosphatidylinositol phosphates is implicated in key physiological functions and pathologies. By contrast, little is known as to how phosphatidylinositol (PI) lipid acyl chains contribute to cellular processes. Here, by employing a mass-spectrometry-based method, we show a role for PI acyl group chains in regulating NLRP3 inflammasome activation in cells lacking ABC transporter ABCB1. In response to canonical stimuli, Abcb1 -/- cells revealed defective priming and activation of the NLRP3 inflammasome owing to blunted TLR-dependent signalling. Cellular lipidomics demonstrated that ABC transporter deficiency shifted the total PI balance such that Abcb1 -/- cells exhibited reduced ratio of the short-chain to long-chain acyl chain lipids. Changes in PI acyl chain configuration accompanied diminished levels of ganglioside GM1, a marker of cholesterol-rich membrane microdomains, in deficient cells. Strikingly, this was not due to differences in the expression of enzymes that either synthesize PI or are involved in acyl chain remodelling. Our study thus suggests an important role for PI lipid chains in priming and activation of the NLRP3 inflammasome thereby highlighting the metabolic regulation of immune responses.
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Journal articlePrasad H, Shenoy AR, Visweswariah SS, 2020,
Cyclic nucleotides, gut physiology and inflammation
, The Federation of European Biochemical Societies (FEBS) Journal, Vol: 287, Pages: 1970-1981, ISSN: 1742-464XMisregulation of gut function and homeostasis impinges on the overall well‐being of the entire organism. Diarrheal disease is the second leading cause of death in children under 5 years of age, and globally, 1.7 billion cases of childhood diarrhea are reported every year. Accompanying diarrheal episodes are a number of secondary effects in gut physiology and structure, such as erosion of the mucosal barrier that lines the gut, facilitating further inflammation of the gut in response to the normal microbiome. Here, we focus on pathogenic bacteria‐mediated diarrhea, emphasizing the role of cyclic adenosine 3',5'‐monophosphate and cyclic guanosine 3′,5′‐monophosphate in driving signaling outputs that result in the secretion of water and ions from the epithelial cells of the gut. We also speculate on how this aberrant efflux and influx of ions could modulate inflammasome signaling, and therefore cell survival and maintenance of gut architecture and function.
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Journal articleWalter A, Unsleber S, Rismondo J, et al., 2020,
Phosphoglycerol-type wall- and lipoteichoic acids are enantiomeric polymers differentially cleaved by the stereospecific glycerophosphodiesterase GlpQ
<jats:title>ABSTRACT</jats:title><jats:p>The cell envelope of Gram-positive bacteria generally comprises two types of polyanionic polymers, either linked to peptidoglycan, wall teichoic acids (WTA), or to membrane glycolipids, lipoteichoic acids (LTA). In some bacteria, including<jats:italic>Bacillus subtilis</jats:italic>strain 168, WTA and LTA both are glycerolphosphate polymers, yet are synthesized by different pathways and have distinct, although not entirely understood morphogenetic functions during cell elongation and division. We show here that the exo-lytic<jats:italic>sn</jats:italic>-glycerol-3-phosphodiesterase GlpQ can discriminate between<jats:italic>B. subtilis</jats:italic>WTA and LTA polymers. GlpQ completely degrades WTA, lacking modifications at the glycerol residues, by sequentially removing glycerolphosphates from the free end of the polymer up to the peptidoglycan linker. In contrast, GlpQ is unable to cleave unmodified LTA. LTA can only be hydrolyzed by GlpQ when the polymer is partially pre-cleaved, thereby allowing GlpQ to get access to the end of the polymer that is usually protected by a connection to the lipid anchor. This indicates that WTA and LTA are enantiomeric polymers: WTA is made of<jats:italic>sn</jats:italic>-glycerol-3-phosphate and LTA is made of<jats:italic>sn</jats:italic>-glycerol-1-phosphate. Differences in stereochemistry between WTA and LTA were assumed based on differences in biosynthesis precursors and chemical degradation products, but so far had not been demonstrated directly by differential, enantioselective cleavage of isolated polymers. The discriminative stereochemistry impacts the dissimilar physiological and immunogenic properties of WTA and LTA and enables independent degradation of the polymers, while appearing in the same location; e.g. under phosphate limitation,<jats:italic>B. subtilis</jats:italic>168 specifically hyd
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Journal articlePanagi I, Jennings E, Zeng J, et al., 2020,
Salmonella effector SteE converts the mammalian serine/threonine kinase GSK3 into a tyrosine kinase to direct macrophage polarization.
, Cell Host and Microbe, Vol: 27, Pages: 41-53.e6, ISSN: 1931-3128Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. In addition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatory transcriptional response in macrophages through its effector protein SteE. However, the target(s) and molecular mechanism of SteE remain unknown. Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. SteE itself is a substrate of GSK3, and phosphorylation of SteE is required for its activity. Remarkably, phosphorylated SteE then forces GSK3 to phosphorylate the non-canonical substrate signal transducer and activator of transcription 3 (STAT3) on tyrosine-705. This results in STAT3 activation, which along with GSK3 is required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker interleukin-4Rα (IL-4Rα). Overall, the conversion of GSK3 to a tyrosine-directed kinase represents a tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment.
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Journal articlePham THM, Brewer SM, Thurston T, et al., 2020,
Salmonella-driven polarization of granuloma macrophages antagonizes TNF-mediated pathogen restriction during persistent infection
, Cell Host and Microbe, Vol: 27, Pages: 54-67.E5, ISSN: 1931-3128Many intracellular bacteria can establish chronic infection and persist in tissues within granulomas composed of macrophages. Granuloma macrophages exhibit heterogeneous polarization states, or phenotypes, that may be functionally distinct. Here, we elucidate a host-pathogen interaction that controls granuloma macrophage polarization and long-term pathogen persistence during Salmonella Typhimurium ( STm) infection. We show that STm persists within splenic granulomas that are densely populated by CD11b +CD11c +Ly6C + macrophages. STm preferentially persists in granuloma macrophages reprogrammed to an M2 state, in part through the activity of the effector SteE, which contributes to the establishment of persistent infection. We demonstrate that tumor necrosis factor (TNF) signaling limits M2 granuloma macrophage polarization, thereby restricting STm persistence. TNF neutralization shifts granuloma macrophages toward an M2 state and increases bacterial persistence, and these effects are partially dependent on SteE activity. Thus, manipulating granuloma macrophage polarization represents a strategy for intracellular bacteria to overcome host restriction during persistent infection.
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Journal articleSequeira RP, McDonald JAK, Marchesi JR, et al., 2020,
Commensal Bacteroidetes protect against Klebsiella pneumoniae colonization and transmission through IL-36 signalling
, Nature Microbiology, Vol: 5, Pages: 313-313, ISSN: 2058-5276The microbiota primes immune defences but the identity of specific commensal microorganisms that protect against infection is unclear. Conversely, how pathogens compete with the microbiota to establish their host niche is also poorly understood. In the present study, we investigate the antagonism between the microbiota and Klebsiella pneumoniae during colonization and transmission. We discover that maturation of the microbiota drives the development of distinct immune defence programmes in the upper airways and intestine to limit K. pneumoniae colonization within these niches. Immune protection in the intestine depends on the development of Bacteroidetes, interleukin (IL)-36 signalling and macrophages. This effect of Bacteroidetes requires the polysaccharide utilization locus of their conserved commensal colonization factor. Conversely, in the upper airways, Proteobacteria prime immunity through IL-17A, but K. pneumoniae overcomes these defences through encapsulation to effectively colonize this site. Ultimately, we find that host-to-host spread of K. pneumoniae occurs principally from its intestinal reservoir, and that commensal-colonization-factor-producing Bacteroidetes are sufficient to prevent transmission between hosts through IL-36. Thus, our study provides mechanistic insight into when, where and how commensal Bacteroidetes protect against K. pneumoniae colonization and contagion, providing insight into how these protective microorganisms could be harnessed to confer population-level protection against K. pneumoniae infection.
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Journal articleDortet L, Broda A, bernabeu S, et al., 2020,
Optimization of the MALDIxin test for the rapid identification of colistin resistance in Klebsiella pneumoniae using MALDI-TOF-MS
, Journal of Antimicrobial Chemotherapy, Vol: 75, Pages: 110-116, ISSN: 0305-7453Background. With the dissemination of carbapenemase producers, a revival of colistin was observed for the treatment of infections caused by multidrug-resistant Gram-negatives. Unfortunately, the increasing usage of colistin led to the emergence of resistance. In Klebsiella pneumoniae, colistin resistance arises through addition of L-arabinose-4N (L-Ara4N) or phosphoethanolamine (pEtN) on the native lipid A. The underlying mechanisms involve numerous chromosome-encoded genes or the plasmid-encoded phosphoethanolamine transferase MCR. Currently, detection of colistin resistance is time consuming since it still relies on MIC determination by broth microdilution. Recently, a rapid diagnostic test based on MALDI-TOF detection of modified lipid A was developed (the MALDIxin test) and tested on Escherichia coli and Acinetobacter baumannii.Objectives. Optimize the MALDIxin test for the rapid detection of colistin resistance in Klebsiella pneumoniae.Methods. This optimization consists on an additional mild-acid hydrolysis of 15 min in 1% acetic acid. The optimized method was tested on a collection of 81 clinical K. pneumoniae isolates including 49 colistin resistant strains among which 45 correspond to chromosome-encoded resistance, 3 MCR-related resistance and one isolate harbouring both mechanisms.Results. The optimized method allowed the rapid (< 30 min) identification of L-Ara4N and pEtN modified lipid A of K. pneumoniae which are known to be the real triggers of polymyxin resistance. In the same time, it discriminates between chromosome-encoded and MCR-related polymyxin resistance.Conclusions. The MALDIxin test has the potential to become an accurate tool for the rapid diagnostic of colistin resistance in clinically-relevant Gram negative bacteria.
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