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(American Journal of Pathology. 2006;168:805-811.)
© 2006 American Society for Investigative Pathology

Nerve Damage in Mycobacterium ulcerans-Infected Mice

Probable Cause of Painlessness in Buruli Ulcer

Masamichi Goto^*, Kazue Nakanaga, Thida Aung^*, Tomofumi Hamada^*, Norishige Yamada^*, Mitsuharu Nomoto^*, Shinichi Kitajima, Norihisa Ishii, Suguru Yonezawa^* and Hajime Saito

From the Department of Human Pathology,^* Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Leprosy Research Center, National Institute of Infectious Diseases Tokyo; the Department of Pathology, Kagoshima University Hospital, Kagoshima; and the Hiroshima Environment and Health Association, Hiroshima, Japan

Buruli ulcer is an emerging chronic painless skin disease found in the tropics and caused by Mycobacterium ulcerans; however, it remains unknown why the large and deep ulcers associated with this disease remain painless. To answer this question, we examined the pathology of BALB/c mice inoculated in the footpads with M. ulcerans African strain 97-107. On days 54 to 70 after inoculation, extensive dermal ulcers, subcutaneous edema, and numerous acid-fast bacilli were noted at the inoculate region. Nerve invasion occurred in the perineurium and extended to the endoneurium, and some nerve bundles were swollen and massively invaded by acid-fast bacilli. However, Schwann cell invasion, a characteristic of leprosy, was not observed. Vacuolar degeneration of myelin-forming Schwann cells was noted in some nerves which may be induced by mycolactone, a toxic lipid produced by M. ulcerans. Polymerase chain reaction analysis of microdissected nerve tissue sections showed positive amplification of M. ulcerans-specific genomic sequences but not of Mycobacterium leprae-specific sequences. Behavioral tests showed decrease of pain until edematous stage, but markedly ulcerated animals showed ordinary response against stimulation. Our study suggests that the painlessness of the disease may be partly due to intraneural invasion of bacilli. Further studies of nerve invasion in clinical samples are urgently needed.

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