Exogenous L‐Alanine promotes phagocytosis of multidrug‐resistant bacterial pathogens

• Published in: EMBO reports 2023-12, Vol.24 (12), p.e49561-n/a
• Main Authors: Jiang, Ming, Chen, Xin‐Hai, Li, Hui, Peng, Xuan‐Xian, Peng, Bo
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Alanine; Animal models; Animals; Bacteria; Bacteria - metabolism; Bacterial infections; Biosynthesis; Coliforms; Dimerization; Drug resistance; E coli; Endocytosis; Fatty acids; Immune response; Infections; Klebsiella; Lipids; Lipopolysaccharides; L‐Alanine; Macrophages; metabolic regulation; Metabolomics; Mice; Multidrug resistance; Multidrug resistant organisms; NF-κB protein; Palmitates; Palmitic acid; Pathogens; Phagocytosis; Phosphatidylinositol 3-Kinases - metabolism; PI3K/Akt and NF‐κB pathway; Proteomics; Public health; Reagents; Survival; TLR4 protein; TLR‐4; Toll-Like Receptor 4 - genetics; Toll-like receptors
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.201949561

Multidrug‐resistant bacteria present a major threat to public health that urgently requires new drugs or treatment approaches. Here, we conduct integrated proteomic and metabolomics analyses to screen for molecular candidates improving survival of mice infected with Vibrio parahaemolyticus, which indicate that L‐Alanine metabolism and phagocytosis are strongly correlated with mouse survival. We also assess the role of L‐Alanine in improving mouse survival by in vivo bacterial challenge experiments using various bacteria species, including V. parahaemolyticus, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Functional studies demonstrate that exogenous L‐Alanine promotes phagocytosis of these multidrug‐resistant pathogen species. We reveal that the underlying mechanism involves two events boosted by L‐Alanine: TLR4 expression and L‐Alanine‐enhanced TLR4 signaling via increased biosynthesis and secretion of fatty acids, including palmitate. Palmitate enhances binding of lipopolysaccharide to TLR4, thereby promoting TLR4 dimer formation and endocytosis for subsequent activation of the PI3K/Akt and NF‐κB pathways and bacteria phagocytosis. Our data suggest that modulation of the metabolic environment is a plausible approach for combating multidrug‐resistant bacteria infection. Synopsis L‐Alanine administration prophylactically and therapeutically protects hosts from infection by multidrug‐resistant bacteria. L‐Alanine enhances the phagocytosis of macrophages by boosting TLR4‐PI3K/AKT‐NFκB signaling and toll‐like receptor 4 expression. L‐Alanine can be used as prophylactic and therapeutic reagents against infection by multidrug‐resistant bacteria. L‐Alanine promotes macrophage phagocytosis of multidrug‐resistant bacteria by increasing the production of fatty acids. Fatty acids enhance LPS‐induced TLR4 dimerization and endocytosis to activate PI3K/AKT and NF‐κB signaling. L‐Alanine upregulates TLR4 expression in macrophages. L‐Alanine administration prophylactically and therapeutically protects hosts from infection by multidrug‐resistant bacteria. L‐Alanine enhances the phagocytosis of macrophages by boosting TLR4‐PI3K/AKT‐NFκB signaling and toll‐like receptor 4 expression.