Sensing Mg²⁺ contributes to the resistance of Pseudomonas aeruginosa to complement‐mediated opsonophagocytosis

Abstract

Pseudomonas aeruginosa adaptation to survive in the host hinges on its ability to probe the environment and respond appropriately. Rapid adaptation is often mediated by two-component regulatory systems, such as the PhoP/PhoQ system that responds to Mg ion concentration. However, there is limited information about the role of PhoQ in P. aeruginosa bloodstream infections. We used a murine model of systemic infection to test the virulence of a PhoQ-deficient mutant. Mutation of PhoQ impaired the virulence and the ability to cause bacteremia of P. aeruginosa. In the presence of blood concentrations of Mg , a PhoQ mutant bound more C3 and was more susceptible to complement-mediated opsonophagocytosis than the parent strain, suggesting a direct effect of the Mg on the modulation of expression of a bacterial component controlled by the PhoP/PhoQ system. Ligand blot analysis, C3 binding experiments and opsonophagocytosis assays identified this component as the outer membrane protein OprH, expression of which impaired the virulence of P. aeruginosa in a murine model of systemic infection. We demonstrate that expression of PhoQ is essential to detect Mg and reduce the expression of OprH, a previously unrecognized C3 binding molecule that promotes the opsonophagocytosis of P. aeruginosa.

Identification of Novel phoP-phoQ Regulated Genes that Contribute to Polymyxin B Tolerance in Pseudomonas aeruginosa

“…A previous study revealed that mutation of phoQ attenuates the bacterial virulence in a murine bacteremia infection model which is due to the upregulation of oprH that serves as a binding target of the complement component C3 [59]. In addition, mutation of phoQ reduces the bacterial twitching motility, biofilm formation, cytotoxicity as well as virulence in a lettuce leaf and a chronic rat lung infection model [34].…”

Bacterial behavior in human blood reveals complement evaders with some persister-like features

“…A plethora of previously identified bacterial factors could interfere with the complement system in the HWB model. Thus, bacteria could alter C3b binding [19,36,55,[57][58][59][60], recruit negative complement regulators [18,20,61,62], break down complement proteins [15,63,64], or stabilize outer membrane integrity [65,66]. Consequently, bacterial resistance to complement activity appears to be multifactorial and strain-dependent, and should thus be investigated in a more systematic and uniform way to obtain a better overall picture of the complex interactions involved.…”

Construction of a Protective Vaccine Against Lipopolysaccharide-Heterologous Pseudomonas aeruginosa Strains Based on Expression Profiling of Outer Membrane Proteins During Infection

“…Previously, it was reported that oprH is highly induced when P. aeruginosa interacts with epithelia cells ( 33 ). Recent studies demonstrated that OprH is a binding target of mammalian surfactant protein A ( 34 ) and C3 complement ( 35 ), indicating accessibility by host factors. In addition, high levels of antibodies against OprH were identified in young children with cystic fibrosis ( 36 ), indicating its high immunogenicity.…”