Sensing cytosolic RpsL by macrophages induces lysosomal cell death and termination of bacterial infection.
PLoS Pathog
; 11(3): e1004704, 2015 Mar.
Article
en En
| MEDLINE
| ID: mdl-25738962
ABSTRACT
The intracellular bacterial pathogen Legionella pneumophila provokes strong host responses and has proven to be a valuable model for the discovery of novel immunosurveillance pathways. Our previous work revealed that an environmental isolate of L. pneumophila induces a noncanonical form of cell death, leading to restriction of bacterial replication in primary mouse macrophages. Here we show that such restriction also occurs in infections with wild type clinical isolates. Importantly, we found that a lysine to arginine mutation at residue 88 (K88R) in the ribosome protein RpsL that not only confers bacterial resistance to streptomycin, but more importantly, severely attenuated the induction of host cell death and enabled L. pneumophila to replicate in primary mouse macrophages. Although conferring similar resistance to streptomycin, a K43N mutation in RpsL does not allow productive intracellular bacterial replication. Further analysis indicated that RpsL is capable of effectively inducing macrophage death via a pathway involved in lysosomal membrane permeabilization; the K88R mutant elicits similar responses but is less potent. Moreover, cathepsin B, a lysosomal protease that causes cell death after being released into the cytosol upon the loss of membrane integrity, is required for efficient RpsL-induced macrophage death. Furthermore, despite the critical role of cathepsin B in delaying RpsL-induced cell death, macrophages lacking cathepsin B do not support productive intracellular replication of L. pneumophila harboring wild type RpsL. This suggests the involvement of other yet unidentified components in the restriction of bacterial replication. Our results identified RpsL as a regulator in the interactions between bacteria such as L. pneumophila and primary mouse macrophages by triggering unique cellular pathways that restrict intracellular bacterial replication.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Ribosómicas
/
Proteínas Bacterianas
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Enfermedad de los Legionarios
/
Macrófagos
Límite:
Animals
Idioma:
En
Revista:
PLoS Pathog
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos