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Cell. 2014 Jun 19;157(7):1565-76. doi: 10.1016/j.cell.2014.04.040.

Mycobacterial toxin induces analgesia in buruli ulcer by targeting the angiotensin pathways.

Author information

1
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.
2
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.
3
Inserm Avenir, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea.
4
UPRES - EA 3143, Laboratoire de Neurobiologie et Transgénèse, 4 rue Larrey 49, 933 Angers, France.
5
Inserm 1083, CNRS UMR6214, Laboratoire de Biologie Neurovasculaire et Mitochondriale Intégrée, 4 rue Larrey 49, 933 Angers, France.
6
Inserm U1063, Stress Oxydant et Pathologies Métaboliques, 4 rue Larrey 49, 933 Angers, France.
7
Laboratoire d'anatomie pathologique, 4 rue Larrey 49, 933 Angers, France.
8
ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Str. 10, 8093 Zürich, 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, Université Nice Sophia Antipolis, Parc Valrose, 06108 Nice, France.
11
Equipe 7, Inserm U892, CNRS U6299, Université et CHU, CRCNA, 4 rue Larrey 49, 933 Angers, France.
12
Unité de Bioinformatique Structurale, CNRS UMR3528 Institut Pasteur, 75015 Paris, France.
13
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.
14
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.

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.

PMID:
24949969
DOI:
10.1016/j.cell.2014.04.040
[Indexed for MEDLINE]
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