Journal article
Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis
M Speir, KE Lawlor, SP Glaser, G Abraham, S Chow, A Vogrin, KE Schulze, R Schuelein, LA OReilly, K Mason, EL Hartland, T Lithgow, A Strasser, G Lessene, DCS Huang, JE Vince, T Naderer
Nature Microbiology | NATURE PUBLISHING GROUP | Published : 2016
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 pr..
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Awarded by National Health and Medical Research Council
Funding Acknowledgements
The authors thank members of the Monash Micro Imaging facility for their technical support, D. Newman (Monash University) for the statistical analysis, E. Latz (University of Bonn) for immortalized C57Bl/6 macrophages and D. Vaux, J. Silke, W. Alexander, S. Masters, L. Lindqvist and P. Bouillet (Walter and Eliza Hall Institute of Medical Research) for providing mice or reagents. This study was funded by grants and fellowships from the NHMRC (Canberra, Australia), programme grants 606788 (T.L. and E.L.H.) and 1016701 (A. S.), project grants 1024839 (T.N. and J.E.V.), 1051235 (S.P.G.) and 1009145 (L.O.R.), CDF1 fellowships 1052598 (J.E.V.) and 1020363 (A. S.), an NHMRC infrastructure grant, Independent Research Institutes Infrastructure Support Scheme grant 361646, the Victorian State Government (OIS grant) and the Leukemia and Lymphoma Society (SCOR grants 7413 and 7001-13).