Journal
NATURE MICROBIOLOGY
Volume 1, Issue 3, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NMICROBIOL.2015.34
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Funding
- NHMRC (Canberra, Australia) [606788, 1016701, 1024839, 1051235, 1009145]
- CDF1 fellowships [1052598, 1020363]
- NHMRC infrastructure grant
- Independent Research Institutes Infrastructure Support Scheme grant [361646]
- Victorian State Government (OIS grant)
- Leukemia and Lymphoma Society (SCOR) [7413, 7001-13]
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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.
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