Pseudomonas aeruginosa lasR-deficient mutant contributes to bacterial virulence through enhancing the PhoB-mediated pathway in response to host environment.

UNLABELLED: Pseudomonas aeruginosa is a major opportunistic pathogen that causes lung infections in patients with cystic fibrosis and chronic obstructive pulmonary disease. Loss-of-function mutations in the quorum-sensing regulatory gene lasR commonly arise during chronic infections, which are associated with exaggerated inflammation and accelerated decline in lung function. Here, in a murine cutaneous abscess model, infection with a ΔlasR mutant or a wild-type-ΔlasR mutant-mixed population resulted in higher bacterial loads and more severe tissue damage than infection by the wild-type strain. The Rhl and PQS quorum-sensing system genes, as well as phospholipase genes, were upregulated in the ΔlasR mutant and the wild-type-ΔlasR mutant-mixed population, which is mediated by PhoB in response to the in vitro and in vivo low-phosphate environments. We further demonstrate an auto-regulatory mechanism of PhoB and identify two LasR-regulated small RNAs that directly repress the translation of phoB. Overall, our results reveal a novel regulatory mechanism whereby mutation of lasR increases the pathogenesis of P. aeruginosa, providing an explanation for the more severe course of infection with the appearance of lasR-defective mutants.

IMPORTANCE: Pseudomonas aeruginosa is an opportunistic pathogen that causes life-threatening infections. The bacterial quorum-sensing systems play important roles in coordinating gene expression during infection. Loss-of-function mutations in a quorum-sensing regulator gene lasR are commonly found in clinical isolates, which are associated with more rapid lung function decline. Here, in a murine cutaneous abscess model, we demonstrate that the presence of a lasR-defective mutant results in hyperproduction of virulence factors, increased antibiotic resistance, and more severe tissue damage, which resembles the human circumstance. We further identify the host environment signal and a novel regulatory pathway whereby mutation of lasR increases the bacterial pathogenesis. Our findings offer new insights into the LasR-mediated regulatory network in response to the host environment and provide clues to understand the lung disease progression driven by lasR-defective mutants.