The Pseudomonas aeruginosa PhoP-PhoQ Two-Component Regulatory System Is Induced upon Interaction with Epithelial Cells and Controls Cytotoxicity

The adaptation of Pseudomonas aeruginosa to its environment, including the host, is tightly controlled by its network of regula-tory systems. The two-component regulatory system PhoPQ has been shown to play a role in the virulence and polymyxin resis-tance of P. aeruginosa as well as several other Gram-negative species. Dysregulation of this system has been demonstrated in clinical isolates, yet how it affects virulence of P. aeruginosa is unknown. To investigate this, an assay was used whereby bacteria were cocultured with human bronchial epithelial cells. The interaction of wild-type (WT) bacteria that had adhered to epithelial cells led to a large upregulation of the expression of the oprH-phoP-phoQ operon and its target, the arn lipopolysaccharide (LPS) modification operon, in a PhoQ-dependent manner, compared to cells in the supernatant that had failed to adhere. Relative to the wild type, a phoQmutant cocultured on epithelial cells produced less secreted protease and lipase and, like the phoQmutant, piv, lipH, and lasBmutants demonstrated reduced cytotoxicity toward epithelial cells. Mutation in phoQ also resulted in altera-tions to lipid A and to increased inflammatory LPS. These data indicate that mutation of phoQ results in a phenotype that is sim-ilar to the less virulent but more inflammatory phenotype of clinical strains isolated from chronic-stage cystic fibrosis lung infections. Pseudomonas aeruginosa is a Gram-negative soil bacterium thatcauses opportunistic infections of plants and animals. While rarely causing infections in healthy humans, P. aeruginosa is the third most common cause of nosocomial infections in the Unite