Within-host evolution of a transcriptional regulator contributes to the establishment of chronic Pseudomonas aeruginosa infection.

As an opportunistic pathogen, Pseudomonas aeruginosa can cause both acute and chronic infections that are notoriously difficult to treat. However, the mechanism underlying acute or chronic P. aeruginosa infection remains unclear. Here, we identify a mutation in a transcriptional regulator PA5438 (named GavR). This mutation causes a 3-amino-acid absence in GavR and is strongly associated with chronic P. aeruginosa infection. Mechanistically, the deletion in GavR directly downregulates the transcription of the aceEF operon and leads to an accumulation of intracellular pyruvate, which can promote bacterial survival in neutrophils. Notably, P. aeruginosa with 9-bp-deleted or full-length gavR composes a mixed population in most patients with chronic or acute infections. Overall, the mutation in gavR attenuates P. aeruginosa virulence and enhances innate immune evasion by reprogramming pyruvate metabolism and the glyoxylate cycle. This work reveals a molecular mechanism of transition control from acute to chronic infection in P. aeruginosa.