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Infection and Immunity, October 2005, p. 6299-6310, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6299-6310.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Infection with Mycobacterium ulcerans Induces Persistent Inflammatory Responses in Mice

Martinha S. Oliveira,1,{dagger} Alexandra G. Fraga,1,{dagger} Egídio Torrado,1 António G. Castro,1 João P. Pereira,1 Adhemar Longatto Filho,1,2 Fernanda Milanezi,1,3 Fernando C. Schmitt,1,3 Wayne M. Meyers,4 Françoise Portaels,5 Manuel T. Silva,1,6 and Jorge Pedrosa1*

Life and Health Sciences Research Institute, School of Health Sciences (ICVS), University of Minho, Braga, Portugal,1 Division of Pathology of Adolfo Lutz Institute, São Paulo, Brazil,2 Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal,3 Armed Forces Institute of Pathology, Washington, D.C.,4 Mycobacteriology Unit, Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium,5 Institute for Molecular and Cell Biology, Porto, Portugal6

Received 7 January 2005/ Returned for modification 11 February 2005/ Accepted 31 May 2005

Buruli ulcer (BU) is a devastating, necrotizing, tropical skin disease caused by infections with Mycobacterium ulcerans. In contrast to other mycobacterioses, BU has been associated with minimal or absent inflammation. However, here we show that in the mouse M. ulcerans induces persistent inflammatory responses with virulence-dependent patterns. Mycolactone-positive, cytotoxic strains are virulent for mice and multiply progressively, inducing both early and persistent acute inflammatory responses. The cytotoxicity of these strains leads to progressive destruction of the inflammatory infiltrates by postapoptotic secondary necrosis, generating necrotic acellular areas with extracellular bacilli released by the lysis of infected phagocytes. The necrotic areas, always surrounded by acute inflammatory infiltrates, expand through the progressive invasion of healthy tissues around the initial necrotic lesions by bacteria and by newly recruited acute inflammatory cells. Our observations show that the lack of inflammatory infiltrates in the extensive areas of necrosis seen in advanced infections results from the destruction of continuously produced inflammatory infiltrates and not from M. ulcerans-induced local or systemic immunosuppression. Whether this is the mechanism behind the predominance of minimal or absent inflammatory responses in BU biopsies remains to be elucidated.

* Corresponding author. Mailing address: Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, 4710-057 Braga, Portugal. Phone: 351-253-604833. Fax: 351-253-604809. E-mail: jpedrosa{at}ecsaude.uminho.pt.

Editor: J. L. Flynn

{dagger} M.S.O. and A.G.F. contributed equally to this work.

Infection and Immunity, October 2005, p. 6299-6310, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6299-6310.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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