Characterization of a key signal transduction pathway involved in virulence regulation in Pseudomonas aeruginosa

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2016, 2017
Yadav, Anjali
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ACS Infectious Diseases, BMC Pulmonary Medicine, Journal of Membrane Biology
Pseudomonas aeruginosa is the leading cause of morbidity and mortality in patients with chronic diseases, neutropenia and those with immunocompromise. Pulmonary infection with P. aeruginosa in patients with cystic fibrosis can result in respiratory failure and death. The pathogenesis of P. aeruginosa involves a lifestyle change in the bacterium and depends on coordination between two-component regulatory systems, quorum sensing systems and signaling via small molecules such as bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP). Acute form of P. aeruginosa infection is characterized by motility and host-directed toxicity by Type Three Secretion System (T3SS). On the other hand, chronic infection is characterized by formation of biofilms. These biofilms are highly resistant to external stressors and play a role in bacterial persistence. RetS-GacS/A-PA1611-RsmA/Y/Z is a key regulatory pathway in P. aeruginosa that determines the bacterium’s lifestyle choice. Previously, PA1611 a hybrid sensor kinase was identified as a new player in this pathway that functions independent of phosphorelay and influences biofilm formation and T3SS. However, the exact nature of its interaction, the regulation and the environmental signals that activate PA1611 are still unexplored. In this study, using advanced molecular methods, the structural and mechanistic basis of the interaction between PA1611 and RetS is examined in P. aeruginosa PAO1. The histidine kinase A and histidine kinase-like ATPase domains of PA1611 are found to play crucial roles in the PA1611–RetS interaction and have been shown to exert profound effect on bacterial phenotypes. cmpX (PA1775) was identified as the regulator of PA1611. A cmpX knockout demonstrated higher biofilm formation, downregulation of the T3SS and elevated intracellular c-di-GMP levels. cmpX was also identified to exert its effects via both the RetS-GacS/A-PA1611-RsmA/Y/Z as well as via activated c-di-GMP signaling. Finally, mucin and anoxia were identified as activators of PA1611 expression as well as shown to facilitate biofilm formation in PAK strain of P. aeruginosa. Collectively, these findings provide a significant and complex role for PA1611 in P. aeruginosa virulence. Understanding TCS function and the environmental signals that they respond to are key to controlling infections with P. aeruginosa and eventually improving disease outcomes.
Pseudomonas aeruginosa, Two component regulatory systems (TCS)
Bhagirath AY, Somayajula D, Li Y, Duan K. (2017) CmpX in Pseudomonas aeruginosa through the Gac/Rsm signaling pathway and by modulating c-di-GMP levels. The Journal of Membrane Biology DOI: 10.1007/s00232-017-9994-6
Bhagirath AY, Pydi SP, Li Y, Lin C, Kong W, Chelikani P, Duan K. (2017) Characterization of the direct interaction between hybrid sensor kinases PA1611 and RetS that controls biofilm formation and the type III secretion system in Pseudomonas aeruginosa. ACS Infectious Diseases; 3(2):162-175
Bhagirath AY, Li Y, Somayajula D, Dadashi M, Badr S, Duan K. (2016) Cystic fibrosis lung environment and Pseudomonas aeruginosa infection. BMC Pulmonary Medicine;16. (1):174