The <i>Pseudomonas aeruginosa</i> effector protein TesG regulates alternative activation of macrophages through NLRC5

<i>Pseudomonas aeruginosa</i> is one of the most common pathogenic bacteria in the clinic. Its large genome and strong genetic plasticity enable it to survive in various environments, posing a significant threat to patient health. We previously identified a key effector protein, TesG, secreted by the type I secretion system, which plays a crucial role in the chronic infection process of <i>P. aeruginosa</i>. However, the underlying mechanism remains incompletely understood. In this study, we newly discovered that TesG can induce alternative activation of macrophages and explored its mechanisms through a series of <i>in vivo</i> and <i>in vitro</i> experiments. We found that TesG promotes the expression of the NLRC5 protein, thereby inducing the polarization of macrophages toward the M2 phenotype. The activation of macrophages induced by TesG primarily occurs through the currently known mechanisms of NLRC5. These findings suggest that <i>P. aeruginosa</i> can regulate the alternative activation of macrophages through the TesG/NLRC5 signaling pathway during chronic infection, significantly aiding its evasion of the host immune system killing. In summary, our data highlight the complex infection strategies developed by pathogenic bacteria to achieve chronic infection.IMPORTANCEDuring the transition from acute to chronic <i>Pseudomonas aeruginosa</i> infection, bacteria modulate the host's immune microenvironment to evade immune responses, ensuring long-term survival. Clinical studies have confirmed that the effector protein TesG (secreted by a type I secretion system) can serve as a potential clinical biomarker for chronic <i>P. aeruginosa</i> lung infections. Our findings indicate that TesG promotes the alternative activation of macrophages through the regulation of NLRC5, thereby suppressing inflammatory responses and facilitating the progression of chronic pulmonary infections. These discoveries enhance our understanding of the complex interplay between <i>P. aeruginosa</i> and the host, laying the groundwork for developing precise diagnostic and therapeutic strategies targeting chronic pulmonary infections.