title: Infection with Mycobacterium ulcerans induces persistent inflammatory responses in mice.
abstract: 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.
authors.affiliation: Life and Health Sciences Research Institute, School of Health Sciences (ICVS), University of Minho, Braga, Portugal.
authors.forename: Martinha S
authors.initials: MS
authors.lastname: Oliveira
authors.forename: Alexandra G
authors.initials: AG
authors.lastname: Fraga
authors.forename: Egídio
authors.initials: E
authors.lastname: Torrado
authors.forename: António G
authors.initials: AG
authors.lastname: Castro
authors.forename: João P
authors.initials: JP
authors.lastname: Pereira
authors.forename: Adhemar Longatto
authors.initials: AL
authors.lastname: Filho
authors.forename: Fernanda
authors.initials: F
authors.lastname: Milanezi
authors.forename: Fernando C
authors.initials: FC
authors.lastname: Schmitt
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Meyers
authors.forename: Françoise
authors.initials: F
authors.lastname: Portaels
authors.forename: Manuel T
authors.initials: MT
authors.lastname: Silva
authors.forename: Jorge
authors.initials: J
authors.lastname: Pedrosa
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003872:Dermatitis / Q000382:microbiology* / Q000473:pathology; D005260:Female; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology / Q000473:pathology*; D019911:Mycobacterium ulcerans / Q000302:isolation & purification / Q000472:pathogenicity*; D009336:Necrosis / Q000382:microbiology / Q000473:pathology; D010538:Peritonitis / Q000382:microbiology* / Q000473:pathology; D014774:Virulence