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.

Suppressive effect of mycolactone-containing fraction from Mycobacterium ulcerans on antibody production against co-administered antigens

“…AT2R blockers inhibit Th 1 and Th 2 immune responses in mice [29,30]. Additionally, mycolactone affects RAW267.4, a macrophage-like mouse cell line, to cause hyperpolarization through AT2R signal inhibition [28]. This relationship between mycolactone and AT2R may also participate in the immunosuppressive role of mycolactone.…”

“…Angiotensin II type 2 receptors (AT2Rs) are also reported as mycolactone-binding proteins [7,28]. AT2R blockers inhibit Th 1 and Th 2 immune responses in mice [29,30].…”

Mixing and matching TREK/TRAAK subunits generate heterodimeric K 2P channels with unique properties

“…TREK1 openers, acting downstream from opioid receptors, might have strong analgesic effects without adverse effects (6). TRAAK may also be a good target for analgesia: Its activation by angiotensin II receptors is responsible for the painless nature of the early lesions of the necrotizing tropical disease Buruli ulcer (7). Also, activation of TREK1 by GABA B receptors in the hippocampus (8), and inhibition of TREK2 by neurotensin receptors in the entorhinal cortex (9), suggests that specific modulators of these channels might also have beneficial actions against drug abuse, and against learning slow down and memory deficits in Alzheimer's disease.…”

The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects

“…The RAS has recently been convincingly linked to the pathophysiology of neuropathic pain [5,84,148,168,202,225], and investigation of the CSF/plasma ratio of angiotensinogen has confirmed local production in the CNS [29]. In this context, it is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a RAS-protein that had the highest discriminatory power between patients and controls.…”