Laurent MARSOLLIER

BURULI ULCER: FROM DISEASE TO PAIN CONTROL

Priscille Brodin1, Ok-Ryul Song1, Estelle Marion2, Yannick Comoglio3, Guillaume Sandoz3, Laurent Marsollier2
1Inserm, Institut Pasteur de Lille, Lille, France
2Inserm, CHU d'Angers, Angers, France
3CNRS, University of Nice, Nice, France

Buruli ulcer is an infectious disease transmitted by arthropod vectors harboring Mycobacterium ulcerans, a mycobacterium which belongs to the same family of bacteria causing tuberculosis and leprosy. The infection causes painless swelling and severe skin lesions. One key feature of M. ulcerans bacterium is its ability to secrete a necrotic toxin, the mycolactone within small lipophilic vesicles, which are critical for the bacterial induced pathogenicity. The biological knowledge as well as the preventive and therapeutic means for this invalidating disease is still very limited.
The extensive skin lesions, 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 that M. ulcerans-induced hypoesthesia is instead achieved through a specific neurological pathway triggered by the secreted mycobacterial polyketide mycolactone, leading to potassium-dependent hyperpolarization of neurons. By use of a combination of siRNA and chemical library image based screening, we showed that mycolactone elicits signaling through type 2 angiotensin II receptors (AT2Rs) leading to the activation of cyclooxygenase I and TRAAK potassium channels, which causes neuron desensitization. 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.