| First Author | Speir M | Year | 2016 |
| Journal | Nat Microbiol | Volume | 1 |
| Pages | 15034 | PubMed ID | 27572165 |
| Mgi Jnum | J:284088 | Mgi Id | MGI:6388211 |
| Doi | 10.1038/NMICROBIOL.2015.34 | Citation | Speir M, et al. (2016) Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis. Nat Microbiol 1:15034 |
| abstractText | 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. |
