송옥렬 (Institut Pasteur de Lille, Universite' d'Angers, 한국파스퇴르연구소) | 한빛사논문 > 한빛사

한빛사논문

조회4,263

Institut Pasteur de Lille, Universite' d'Angers, 한국파스퇴르연구소

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Cell, Volume 157, Issue 7, 19 June 2014, Pages 1565–1576 | DOI: http://dx.doi.org/10.1016/j.cell.2014.04.040 Mycobacterial Toxin Induces Analgesia in Buruli Ulcer by Targeting the Angiotensin Pathways

Abstract

Estelle Marion^{1, 2, 13}, Ok-Ryul Song^{1, 2, 3, 13}, Thierry Christophe^{2, 13}, Jeremie Babonneau², Denis Fenistein², Joel Eyer⁴, Frank Letournel⁴, Daniel Henrion⁵, Nicolas Clere⁶, Vincent Paille⁵, Nathalie C. Guerineau⁵, Jean-Paul Saint Andre⁷, Philipp Gersbach⁸, Karl-Heinz Altmann⁸, Timothy Paul Stinear⁹, Yannick Comoglio¹⁰, Guillaume Sandoz¹⁰, Laurence Preisser¹¹, Yves Delneste¹¹, Edouard Yeramian^{12, 14}, Laurent Marsollier^{1, 2, 11, 14}, Priscille Brodin^{2, 3, 14}

¹ Inserm Avenir, 4 rue Larrey 49, 933 Angers, France
² Inserm Avenir, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea
³ Inserm U1019, CNRS UMR8204, Universite de Lille - Nord de France, Institut Pasteur de Lille, Center for Infection and Immunity, 1, rue du Professeur Calmette, 59000 Lille, France
⁴ UPRES - EA 3143, Laboratoire de Neurobiologie et Transgenese, 4 rue Larrey 49, 933 Angers, France
⁵ Inserm 1083, CNRS UMR6214, Laboratoire de Biologie Neurovasculaire et Mitochondriale Integree, 4 rue Larrey 49, 933 Angers, France
⁶ Inserm U1063, Stress Oxydant et Pathologies Metaboliques, 4 rue Larrey 49, 933 Angers, France
⁷ Laboratoire d’anatomie pathologique, 4 rue Larrey 49, 933 Angers, France
⁸ ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Str. 10, 8093 Zurich, Switzerland
⁹ Department of Microbiology and Immunology, University of Melbourne, Parkville 3010, Australia
¹⁰ Inserm Avenir, Laboratories of Excellence, Ion Channel Science and Therapeutics Nice, Institut de Biologie Valrose, iBV, Inserm U1091, CNRS UMR7277, Universite Nice Sophia Antipolis, Parc Valrose, 06108 Nice, France
¹¹ Equipe 7, Inserm U892, CNRS U6299, Universite et CHU, CRCNA, 4 rue Larrey 49, 933 Angers, France
¹² Unite de Bioinformatique Structurale, CNRS UMR3528 Institut Pasteur, 75015 Paris, France
¹³ Co-first authors
¹⁴ Co-senior authors

Corresponding author : Laurent Marsollier, Priscille Brodin

Summary
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.

논문정보

형식Research article
게재일2014년 06월 (BRIC 등록일 2014-06-24)
연구진국내(교신)+국외 연구진
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