title: Mycolactone is responsible for the painlessness of Mycobacterium ulcerans infection (buruli ulcer) in a murine study.
abstract: Buruli ulcer is a chronic skin disease caused by Mycobacterium ulcerans, which produces a toxic lipid mycolactone. Despite the extensive necrosis and tissue damage, the lesions are painless. This absence of pain prevents patients from seeking early treatment and, as a result, many patients experience severe sequelae, including limb amputation. We have reported that mice inoculated with M. ulcerans show loss of pain sensation and nerve degeneration. However, the molecules responsible for the nerve damage have not been identified. In order to clarify whether mycolactone alone can induce nerve damage, mycolactone A/B was injected to footpads of BALB/c mice. A total of 100 microg of mycolactone induced footpad swelling, redness, and erosion. The von Frey sensory test showed hyperesthesia on day 7, recovery on day 21, and hypoesthesia on day 28. Histologically, the footpads showed epidermal erosion, moderate stromal edema, and moderate neutrophilic infiltration up to day 14, which gradually resolved. Nerve bundles showed intraneural hemorrhage, neutrophilic infiltration, and loss of Schwann cell nuclei on days 7 and 14. Ultrastructurally, vacuolar change of myelin started on day 14 and gradually subsided by day 42, but the density of myelinated fibers remained low. This study demonstrated that initial hyperesthesia is followed by sensory recovery and final hypoesthesia. Our present study suggests that mycolactone directly damages nerves and is responsible for the absence of pain characteristic of Buruli ulcer. Furthermore, mice injected with 200 microg of mycolactone showed pulmonary hemorrhage. This is the first study to demonstrate the systemic effects of mycolactone.
authors.affiliation: Department of Human Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: En
authors.forename: Masamichi
authors.initials: M
authors.lastname: Goto
authors.forename: Kazue
authors.initials: K
authors.lastname: Nakanaga
authors.forename: Michiyo
authors.initials: M
authors.lastname: Higashi
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ishii
authors.forename: Hajime
authors.initials: H
authors.lastname: Saito
authors.forename: Suguru
authors.initials: S
authors.lastname: Yonezawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hamada
authors.forename: Pamela L C
authors.initials: PL
authors.lastname: Small
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D054312:Buruli Ulcer / Q000503:physiopathology*; D005260:Female; D005528:Foot / Q000473:pathology; D006470:Hemorrhage; D006941:Hyperesthesia; D006987:Hypesthesia; D008168:Lung / Q000473:pathology; D018942:Macrolides; D051379:Mice; D008807:Mice, Inbred BALB C; D019911:Mycobacterium ulcerans / Q000378:metabolism*; D009336:Necrosis / Q000473:pathology; D009417:Nerve Tissue / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D012883:Skin Ulcer / Q000473:pathology; D013997:Time Factors
chemical_list: D000700:Analgesics; D001427:Bacterial Toxins; D018942:Macrolides; C117218:mycolactone