A Unique Amino Acid, Se-Met, Regulates Autophagy and Inflammation in Pseudomonas aeruginosa Infection in Mice through the PAK1/Akt1/mTOR and NF-κB Signaling Pathway

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Pseudomonas aeruginosa is a prevalent opportunistic pathogen that poses significant clinical challenges due to its diverse virulence factors and complex resistance mechanisms. Thus, exploring novel drugs against bacterial infections is critical. Here, we report that a unique selenium-containing amino acid (Selenomethionine) has potential for inhibiting P. aeruginosa infections through in vitro experiments. Using P. aeruginosa infection mice models, we further revealed that Se-Met-treated mice exhibited reduced lung damage, decreased systemic bacterial dissemination, lower mortality rates, and suppressed inflammatory responses compared to those infected with PAO1. We demonstrated that Se-Met treatment led to a reduction in the expression of PAK1 in MH-S cells. The suppression of PAK1 resulted in decreased phosphorylation levels of Akt, thereby blocking the Akt-mTOR signaling pathway, which facilitated the release of the ULK1/2-Atg13-FIP200 complex and initiated autophagosome formation. The reduction of PAK1 inhibited the activation of the NF-κB axis, further suppressing the inflammatory response. Together, these findings provide a molecular basis for use of Se-Met to modulate the host immune response against P. aeruginosa infections, suggesting that Se-Met might be a promising candidate for adjunctive therapy of the pathogen-caused infectious diseases.

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