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Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis.
Speir, Mary; Lawlor, Kate E; Glaser, Stefan P; Abraham, Gilu; Chow, Seong; Vogrin, Adam; Schulze, Keith E; Schuelein, Ralf; O'Reilly, Lorraine A; Mason, Kylie; Hartland, Elizabeth L; Lithgow, Trevor; Strasser, Andreas; Lessene, Guillaume; Huang, David C S; Vince, James E; Naderer, Thomas.
Afiliación
  • Speir M; Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
  • Lawlor KE; Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.
  • Glaser SP; Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
  • Abraham G; Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.
  • Chow S; Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
  • Vogrin A; Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
  • Schulze KE; Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
  • Schuelein R; Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
  • O'Reilly LA; Monash Micro Imaging, Monash University, Clayton 3800, Victoria, Australia.
  • Mason K; Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Victoria, Australia.
  • Hartland EL; Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.
  • Lithgow T; Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
  • Strasser A; Department of Medicine, The University of Melbourne, Parkville 3010, Victoria, Australia.
  • Lessene G; Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Victoria, Australia.
  • Huang DC; Department of Microbiology and the Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
  • Vince JE; Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.
  • Naderer T; Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
Nat Microbiol ; 1: 15034, 2016 Feb 24.
Article en En | MEDLINE | ID: mdl-27572165
Human pathogenic Legionella replicate in alveolar macrophages and cause a potentially lethal form of pneumonia known as Legionnaires' disease(1). Here, we have identified a host-directed therapeutic approach to eliminate intracellular Legionella infections. We demonstrate that the genetic deletion, or pharmacological inhibition, of the host cell pro-survival protein BCL-XL induces intrinsic apoptosis of macrophages infected with virulent Legionella strains, thereby abrogating Legionella replication. BCL-XL is essential for the survival of Legionella-infected macrophages due to bacterial inhibition of host-cell protein synthesis, resulting in reduced levels of the short-lived, related BCL-2 pro-survival family member, MCL-1. Consequently, a single dose of a BCL-XL-targeted BH3-mimetic therapy, or myeloid cell-restricted deletion of BCL-XL, limits Legionella replication and prevents lethal lung infections in mice. These results indicate that repurposing BH3-mimetic compounds, originally developed to induce cancer cell apoptosis, may have efficacy in treating Legionnaires' and other diseases caused by intracellular microbes.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Legionella / Macrófagos Alveolares / Apoptosis / Proteína bcl-X Límite: Animals Idioma: En Revista: Nat Microbiol Año: 2016 Tipo del documento: Article País de afiliación: Australia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Legionella / Macrófagos Alveolares / Apoptosis / Proteína bcl-X Límite: Animals Idioma: En Revista: Nat Microbiol Año: 2016 Tipo del documento: Article País de afiliación: Australia