The transcription regulator CodR promotes virulence and antibiotic resistance of Pseudomonas aeruginosa by sensing host-derived choline

During early infection, Pseudomonas aeruginosa degrades phosphatidylcholine (PC) in host respiratory epithelial cells to release choline (Cho), facilitating colonization. However, the regulatory mechanisms underlying Cho metabolism and its role in pathogenesis remain unclear. Here, we identify CodR, a global transcriptional activator from the GcvA family, as a critical regulator of P. aeruginosa pathogenesis. CodR directly senses exogenous Cho, binding it with high affinity to activate the transcription of key virulence-associated genes, including mexA, pslA, and amrZ. Loss of CodR downregulates genes responsible for the type III secretion system (T3SS), PC degradation, extracellular polysaccharide biosynthesis, and siderophore production, leading to reduced biofilm formation and attenuated virulence in a murine pneumonia model. Remarkably, CodR-mediated Cho sensing also upregulates antibiotic resistance genes, enhancing bacterial survival under diverse antibiotic treatments. These findings reveal how CodR integrates host-derived signals to modulate bacterial virulence and antibiotic resistance, offering new insights into host-pathogen interactions and potential therapeutic strategies