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Infection and Immunity, May 2008, p. 2002-2007, Vol. 76, No. 5
0019-9567/08/$08.00+0     doi:10.1128/IAI.01588-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mycolactone Is Responsible for the Painlessness of Mycobacterium ulcerans Infection (Buruli Ulcer) in a Murine Study

Department of Human Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan,¹ National Sanatorium Hoshizuka-Keiaien, Kagoshima, Japan,² Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, Japan,³ Hiroshima Environment and Health Association, Hiroshima, Japan,⁴ Kagoshima University Graduate School of Health Sciences, Kagoshima, Japan,⁵ Department of Microbiology, University of Tennessee, Knoxville, Tennessee 37996-0845⁶

Received 2 December 2007/ Returned for modification 10 January 2008/ Accepted 19 February 2008

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 µg 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 µg of mycolactone showed pulmonary hemorrhage. This is the first study to demonstrate the systemic effects of mycolactone.

Published ahead of print on 3 March 2008.

Editor: F. C. Fang