A Streptococcus pneumoniae endolysin mutant protein ΔA146Ply elicits rapid broad-spectrum mucosal protection in mice via upregulation of GPX4 through TLR4/IRG1/NRF2 to alleviate macrophage ferroptosis.
Free Radic Biol Med
; 222: 344-360, 2024 Sep.
Article
en En
| MEDLINE
| ID: mdl-38945457
ABSTRACT
Innovative solutions for rapid protection against broad-spectrum infections are very important in dealing with complex infection environments. We utilized a functionally inactive mutated endolysin protein of Streptococcus pneumoniae (ΔA146Ply) to immunize mice against pneumonic infections by multidrug-resistant bacteria, Candida albicans and influenza virus type A. ΔA146Ply protection relied on both immunized tissue-resident and monocyte-derived alveolar macrophages and inhibited infection induced ferroptosis that upregulated expression of GPX4 (glutathione peroxidase) in alveolar macrophages. Ferroptosis resistance endowed macrophages with enhanced phagocytosis by inhibiting lipid peroxidation during infection. Moreover, we demonstrated ΔA146Ply upregulated GPX4 through the TLR4/IRG1/NRF2 pathway. ΔA146Ply also induced ferroptosis inhibition and phagocytosis improvement in human monocytes. This mode of action is a novel and potentially prophylactic and rapid broad-spectrum anti-infection mechanism. Our study provides new insights into protective interventions that act by regulating ferroptosis to improve multiple pathogen resistance via GPX4 targeting.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Streptococcus pneumoniae
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Macrófagos Alveolares
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Factor 2 Relacionado con NF-E2
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Receptor Toll-Like 4
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Ferroptosis
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Fosfolípido Hidroperóxido Glutatión Peroxidasa
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Free Radic Biol Med
Asunto de la revista:
BIOQUIMICA
/
MEDICINA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Estados Unidos