The Pseudomonas aeruginosa PAO1 two-component regulator CarSR regulates calcium homeostasis and calciuminduced virulence factor production through its regulatory targets CarO and CarP

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Abstract

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 that P. 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 genomewide transcriptional response of P. 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 called carS and carR), while the closely related two-component regulators phoPQ and pmrAB were repressed by CaCl2 addition. To identify the regulatory targets of CarSR, we constructed a deletion mutant of carR 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 called carO), and the inner membrane-anchored five-bladed β-propeller protein, PA0327 (here called carP). Mutations in both carO and carP affected Ca2+ homeostasis, reducing the ability of P. aeruginosa to export excess Ca2+. In addition, a mutation in carP 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.

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Guragain, M., King, M. M., Williamson, K. S., Pérez-Osorio, A. C., Akiyama, T., Khanam, S., … Franklin, M. J. (2016). The Pseudomonas aeruginosa PAO1 two-component regulator CarSR regulates calcium homeostasis and calciuminduced virulence factor production through its regulatory targets CarO and CarP. Journal of Bacteriology, 198(6), 951–963. https://doi.org/10.1128/JB.00963-15

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