title: Mycobacterial toxin induces analgesia in buruli ulcer by targeting the angiotensin pathways.
abstract: Mycobacterium ulcerans, the etiological agent of Buruli ulcer, causes extensive skin lesions, which despite their severity are not accompanied by pain. It was previously thought that this remarkable analgesia is ensured by direct nerve cell destruction. We demonstrate here that M. ulcerans-induced hypoesthesia is instead achieved through a specific neurological pathway triggered by the secreted mycobacterial polyketide mycolactone. We decipher this pathway at the molecular level, showing that mycolactone elicits signaling through type 2 angiotensin II receptors (AT2Rs), leading to potassium-dependent hyperpolarization of neurons. We further validate the physiological relevance of this mechanism with in vivo studies of pain sensitivity in mice infected with M. ulcerans, following the disruption of the identified pathway. Our findings shed new light on molecular mechanisms evolved by natural systems for the induction of very effective analgesia, opening up the prospect of new families of analgesics derived from such systems.
authors.affiliation: Inserm Avenir, 4 rue Larrey 49, 933 Angers, France; Inserm Avenir, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea.
authors.forename: Estelle
authors.initials: E
authors.lastname: Marion
authors.affiliation: Inserm Avenir, 4 rue Larrey 49, 933 Angers, France; Inserm Avenir, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea; Inserm U1019, CNRS UMR8204, Université de Lille - Nord de France, Institut Pasteur de Lille, Center for Infection and Immunity, 1, rue du Professeur Calmette, 59000 Lille, France.
authors.forename: Ok-Ryul
authors.initials: OR
authors.lastname: Song
authors.affiliation: Inserm Avenir, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea.
authors.forename: Thierry
authors.initials: T
authors.lastname: Christophe
authors.affiliation: Inserm Avenir, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Babonneau
authors.affiliation: Inserm Avenir, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea.
authors.forename: Denis
authors.initials: D
authors.lastname: Fenistein
authors.affiliation: UPRES - EA 3143, Laboratoire de Neurobiologie et Transgénèse, 4 rue Larrey 49, 933 Angers, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Eyer
authors.affiliation: UPRES - EA 3143, Laboratoire de Neurobiologie et Transgénèse, 4 rue Larrey 49, 933 Angers, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Letournel
authors.affiliation: Inserm 1083, CNRS UMR6214, Laboratoire de Biologie Neurovasculaire et Mitochondriale Intégrée, 4 rue Larrey 49, 933 Angers, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.affiliation: Inserm U1063, Stress Oxydant et Pathologies Métaboliques, 4 rue Larrey 49, 933 Angers, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Clere
authors.affiliation: Inserm 1083, CNRS UMR6214, Laboratoire de Biologie Neurovasculaire et Mitochondriale Intégrée, 4 rue Larrey 49, 933 Angers, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Paille
authors.affiliation: Inserm 1083, CNRS UMR6214, Laboratoire de Biologie Neurovasculaire et Mitochondriale Intégrée, 4 rue Larrey 49, 933 Angers, France.
authors.forename: Nathalie C
authors.initials: NC
authors.lastname: Guérineau
authors.affiliation: Laboratoire d'anatomie pathologique, 4 rue Larrey 49, 933 Angers, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Saint André
authors.affiliation: ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Gersbach
authors.affiliation: ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Parkville 3010, Australia.
authors.forename: Timothy Paul
authors.initials: TP
authors.lastname: Stinear
authors.affiliation: Inserm Avenir, Laboratories of Excellence, Ion Channel Science and Therapeutics Nice, Institut de Biologie Valrose, iBV, Inserm U1091, CNRS UMR7277, Université Nice Sophia Antipolis, Parc Valrose, 06108 Nice, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Comoglio
authors.affiliation: Inserm Avenir, Laboratories of Excellence, Ion Channel Science and Therapeutics Nice, Institut de Biologie Valrose, iBV, Inserm U1091, CNRS UMR7277, Université Nice Sophia Antipolis, Parc Valrose, 06108 Nice, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sandoz
authors.affiliation: Equipe 7, Inserm U892, CNRS U6299, Université et CHU, CRCNA, 4 rue Larrey 49, 933 Angers, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Preisser
authors.affiliation: Equipe 7, Inserm U892, CNRS U6299, Université et CHU, CRCNA, 4 rue Larrey 49, 933 Angers, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Delneste
authors.affiliation: Unité de Bioinformatique Structurale, CNRS UMR3528 Institut Pasteur, 75015 Paris, France.
authors.forename: Edouard
authors.initials: E
authors.lastname: Yeramian
authors.affiliation: Inserm Avenir, 4 rue Larrey 49, 933 Angers, France; Inserm Avenir, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea; Equipe 7, Inserm U892, CNRS U6299, Université et CHU, CRCNA, 4 rue Larrey 49, 933 Angers, France. Electronic address: laurent.marsollier@inserm.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Marsollier
authors.affiliation: Inserm Avenir, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea; Inserm U1019, CNRS UMR8204, Université de Lille - Nord de France, Institut Pasteur de Lille, Center for Infection and Immunity, 1, rue du Professeur Calmette, 59000 Lille, France. Electronic address: priscille.brodin@inserm.fr.
authors.forename: Priscille
authors.initials: P
authors.lastname: Brodin
mesh_terms: D000700:Analgesics / Q000302:isolation & purification; D000809:Angiotensins / Q000378:metabolism*; D000818:Animals; D054312:Buruli Ulcer / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D004195:Disease Models, Animal; D004487:Edema / Q000382:microbiology; D006801:Humans; D006987:Hypesthesia / Q000139:chemically induced; D018942:Macrolides / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism; D051379:Mice; D019911:Mycobacterium ulcerans; D009474:Neurons / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000700:Analgesics; D000809:Angiotensins; D018942:Macrolides; D015221:Potassium Channels; D044139:Receptor, Angiotensin, Type 2; C117218:mycolactone; D011451:Prostaglandin-Endoperoxide Synthases