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Pseudomonas aeruginosa is an opportunistic human pathogen that causes severe, life-threatening infections in patients with cystic fibrosis (CF), endocarditis, wounds, or artificial implants. During CF pulmonary infections,P. aeruginosa often encounters environments where the levels of calcium (Ca2+ ) are elevated. Previously, we showed thatP. aeruginosa responds to externally added Ca2+ through enhanced biofilm formation, increased production of several secreted virulence factors, and by developing a transient increase in the intracellular Ca2+ level, followed by its removal to the basal submicromolar level. However, the molecular mechanisms responsible for regulating Ca2+ -induced virulence factor production and Ca2+ homeostasis are not known. Here, we characterized the genome-wide transcriptional response ofP. aeruginosa to elevated [Ca2+ ] in both planktonic cultures and biofilms. Among the genes induced by CaCl2 in strain PAO1 was an operon containing the two-component regulator PA2656-PA2657 (here calledcarS andcarR ), while the closely related two-component regulatorsphoPQ andpmrAB were repressed by CaCl2 addition. To identify the regulatory targets of CarSR, we constructed a deletion mutant ofcarR and performed transcriptome analysis of the mutant strain at low and high [Ca2+ ]. Among the genes regulated by CarSR in response to CaCl2 are the predicted periplasmic OB-fold protein, PA0320 (here calledcarO ), and the inner membrane-anchored five-bladed β-propeller protein, PA0327 (here calledcarP ). Mutations in bothcarO andcarP affected Ca2+ homeostasis, reducing the ability ofP. aeruginosa to export excess Ca2+ . In addition, a mutation incarP had a pleotropic effect in a Ca2+ -dependent manner, altering swarming motility, pyocyanin production, and tobramycin sensitivity. Overall, the results indicate that the two-component system CarSR is responsible for sensing high levels of external Ca2+ and responding through its regulatory targets that modulate Ca2+ homeostasis, surface-associated motility, and the production of the virulence factor pyocyanin.IMPORTANCE During infectious disease,Pseudomonas aeruginosa encounters environments with high calcium (Ca2+ ) concentrations, yet the cells maintain intracellular Ca2+ at levels that are orders of magnitude less than that of the external environment. In addition, Ca2+ signalsP. aeruginosa to induce the production of several virulence factors. Compared to eukaryotes, little is known about how bacteria maintain Ca2+ homeostasis or how Ca2+ acts as a signal. In this study, we identified a two-component regulatory system inP. aeruginosa PAO1, termed CarRS, that is induced at elevated Ca2+ levels. CarRS modulates Ca2+ signaling and Ca2+ homeostasis through its regulatory targets, CarO and CarP. The results demonstrate thatP. aeruginosa uses a two-component regulatory system to sense external Ca2+ and relays that information for Ca2+ -dependent cellular processes.

journal of bacteriology

The Pseudomonas aeruginosa PAO1 Two-Component Regulator CarSR Regulates Calcium Homeostasis and Calcium-Induced Virulence Factor Production through Its Regulatory Targets CarO and CarP