title: Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis.
abstract: 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.
authors: Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
authors: Mary
authors: M
authors: Speir
authors: Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors: Kate E
authors: KE
authors: Lawlor
authors: Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors: Stefan P
authors: SP
authors: Glaser
authors: Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
authors: Gilu
authors: G
authors: Abraham
authors: Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
authors: Seong
authors: http://orcid.org/0000-0002-4392-3863
authors: S
authors: Chow
authors: Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
authors: Adam
authors: A
authors: Vogrin
authors: Monash Micro Imaging, Monash University, Clayton 3800, Victoria, Australia.
authors: Keith E
authors: KE
authors: Schulze
authors: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Victoria, Australia.
authors: Ralf
authors: R
authors: Schuelein
authors: Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors: Lorraine A
authors: LA
authors: O'Reilly
authors: Department of Medicine, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors: Kylie
authors: K
authors: Mason
authors: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Victoria, Australia.
authors: Elizabeth L
authors: EL
authors: Hartland
authors: Department of Microbiology and the Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
authors: Trevor
authors: T
authors: Lithgow
authors: Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors: Andreas
authors: A
authors: Strasser
authors: Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors: Guillaume
authors: G
authors: Lessene
authors: Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors: David C S
authors: DC
authors: Huang
authors: Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors: James E
authors: JE
authors: Vince
authors: Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
authors: Thomas
authors: T
authors: Naderer
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D017353:Gene Deletion; D007875:Legionella / Q000254:growth & development*; D007876:Legionellosis / Q000517:prevention & control; D016676:Macrophages, Alveolar / Q000382:microbiology* / Q000502:physiology*; D051379:Mice; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C494812:Bcl2l1 protein, mouse; D051020:bcl-X Protein