Staphylococcus aureus induces an itaconate-dominated immunometabolic response that drives biofilm formation.
Kira L. Tomlinson,Tania Wong Fok Lung,Felix Dach,Felix Dach,Medini K. Annavajhala,Stanislaw J. Gabryszewski,Ryan A. Groves,Marija Drikic,Nancy Francoeur,Shwetha Hara Sridhar,Melissa Smith,Sara Khanal,Clemente J. Britto,Robert Sebra,Ian A. Lewis,Anne-Catrin Uhlemann,Barbara C. Kahl,Alice Prince,Sebastián A. Riquelme +18 more
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TLDR
It is shown that, in contrast to Gram-negative pathogens, S. aureus induces a distinct airway immunometabolic response dominated by the release of the electrophilic metabolite, itaconate, which adapts to theItaconate-dominated immunometabolism by producing biofilms, which are associated with chronic infection of the human airway.Abstract:
Staphylococcus aureus is a prominent human pathogen that readily adapts to host immune defenses. Here, we show that, in contrast to Gram-negative pathogens, S. aureus induces a distinct airway immunometabolic response dominated by the release of the electrophilic metabolite, itaconate. The itaconate synthetic enzyme, IRG1, is activated by host mitochondrial stress, which is induced by staphylococcal glycolysis. Itaconate inhibits S. aureus glycolysis and selects for strains that re-direct carbon flux to fuel extracellular polysaccharide (EPS) synthesis and biofilm formation. Itaconate-adapted strains, as illustrated by S. aureus isolates from chronic airway infection, exhibit decreased glycolytic activity, high EPS production, and proficient biofilm formation even before itaconate stimulation. S. aureus thus adapts to the itaconate-dominated immunometabolic response by producing biofilms, which are associated with chronic infection of the human airway. The authors show that the pathogen Staphylococcus aureus induces a distinct airway immunometabolic response, dominated by release of itaconate. This metabolite, in turn, potentiates extracellular polysaccharide synthesis and biofilm formation in S. aureus, which may facilitate chronic infection.read more
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Journal ArticleDOI
The role of itaconate in host defense and inflammation
TL;DR: Itaconate has been shown to have anti-inflammatory effects in preclinical models of sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, and pulmonary fibrosis as mentioned in this paper .
Journal ArticleDOI
The role of itaconate in host defense and inflammation
TL;DR: Itaconate and its derivatives have antiinflammatory effects in preclinical models of sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, and pulmonary fibrosis, pointing to possible itaconate-based therapeutics for a range of inflammatory diseases.
Journal ArticleDOI
Staphylococcus aureus host interactions and adaptation
Benjamin P Howden,Stefano Giulieri,Tania Wong Fok Lung,Sarah L. Baines,Liam K. R. Sharkey,Jean Y. H. Lee,Abderrahman Hachani,Ian R. Monk,Timothy P. Stinear +8 more
TL;DR: Invasive Staphylococcus aureus infections are common, causing high mortality, compounded by the propensity of the bacterium to develop drug resistance as discussed by the authors , and this interplay is multidimensional and evolving.
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Immunometabolic crosstalk during bacterial infection
TL;DR: In this article , the authors review mechanisms by which host immunometabolites regulate bacterial pathogenicity and discuss opportunities for the development of therapeutics targeting metabolic host-pathogen crosstalk.
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TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages
Ev-Marie Schuster,Maximilian W. Epple,Katharina M. Glaser,Michael Mihlan,Kerstin Lucht,Julia A Zimmermann,Anna Bremser,Aikaterini Polyzou,Nadine Obier,Nina Cabezas-Wallscheid,Eirini Trompouki,Andrea Ballabio,Jörg Vogel,Joerg Martin Buescher,Alexander J. Westermann,Angelika S. Rambold +15 more
TL;DR: In this paper , the lysosomal biogenesis factor transcription factor EB (TFEB) was identified as regulator for phago-lysosome-mitochondria crosstalk in macrophages.
References
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Journal ArticleDOI
Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1.
Evanna L. Mills,Dylan G. Ryan,Hiran A. Prag,Dina Dikovskaya,Deepthi Menon,Zbigniew Zaslona,Mark P. Jedrychowski,Ana S. H. Costa,Maureen Higgins,Emily Hams,John Szpyt,Marah C. Runtsch,Martin S. King,Joanna F. McGouran,Roman Fischer,Benedikt M. Kessler,Anne F. McGettrick,Mark M. Hughes,Richard G. Carroll,Richard G. Carroll,Lee M. Booty,Lee M. Booty,Elena V. Knatko,Paul J. Meakin,Michael L.J. Ashford,Louise K. Modis,Gino Brunori,Daniel C. Sévin,Padraic G. Fallon,Stuart T. Caldwell,Edmund R.S. Kunji,Edward T. Chouchani,Christian Frezza,Albena T. Dinkova-Kostova,Albena T. Dinkova-Kostova,Richard C. Hartley,Michael P. Murphy,Luke A. J. O'Neill,Luke A. J. O'Neill +38 more
TL;DR: It is shown that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 by lipopolysaccharide in mouse and human macrophages and that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconates production.
Journal ArticleDOI
Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation
Vicky Lampropoulou,Alexey Sergushichev,Monika Bambouskova,Sharmila Nair,Emma E. Vincent,Ekaterina Loginicheva,Luisa Cervantes-Barragan,Xiucui Ma,Stanley Ching-Cheng Huang,Takla Griss,Carla J. Weinheimer,Shabaana A. Khader,Gwendalyn J. Randolph,Edward J. Pearce,Russell G. Jones,Abhinav Diwan,Michael S. Diamond,Maxim N. Artyomov +17 more
TL;DR: It is shown that itaconate modulates macrophage metabolism and effector functions by inhibiting succinate dehydrogenase-mediated oxidation of succinate, and this action exerts anti-inflammatory effects when administered in vitro and in vivo during Macrophage activation and ischemia-reperfusion injury.
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