Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis.
Nat Microbiol
; 1: 15034, 2016 Feb 24.
Article
em En
| MEDLINE
| ID: mdl-27572165
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Legionella
/
Macrófagos Alveolares
/
Apoptose
/
Proteína bcl-X
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Austrália