Early stages of host invasion by Pseudomonas Aeruginosa and effect of cyclic Diguanylate signaling

Abstract

Pseudomonas aeruginosa is a significant cause of hospital-acquired infections as it can thrive on most surfaces (biotic and abiotic), use a wide range of organic material as nutrition and is highly adaptable to changes in its environment. Bacterial invasion plays a critical role in the establishment of P. aeruginosa infection, which involves surface attachment of bacteria on the host cells followed by internalization/ tissue penetration. Thus it is important to identify targets involved in this critical step to prevent disease initiation and progression. Major virulence factors aiding bacterial invasion are surface appendages and secreted proteases. The second messenger cyclic diguanylate (c-di-GMP) is well known to affect attachment of bacteria to surfaces, biofilm formation and related virulence phenomena. MorA, a global regulator containing a GGDEF-EAL domain has been previously shown to affect biofilm formation and timing of flagellar biogenesis in P. aeruginosa PAO1 strain, and fimbriae expression in other clinical strains. These domains are implicated in the turnover of c-di-GMP. This study provides evidence that the global regulator MorA affects P. aeruginosa attachment to host surface and levels of proteases secreted by the type II secretion system (T2SS), thus regulating the invasion capacity of the pathogen. This is the first report on control of c-di-GMP signaling on this secretion system. It was postulated that there may be a common post-transcriptional signal acting between the regulator MorA and the effectors i.e. T2SS and pili/flagella, since all the three are located at the bacterial poles. Owing to growing importance of Ser/ Thr/ Tyr protein phosphorylation in bacteria, it was hypothesized to be the bridging phenomenon. A comprehensive phosphoproteome analysis on P. aeruginosa and P. putida revealed several interesting leads suggesting regulation of many virulence and survival mechanisms by protein phosphorylation. Thus, this analysis uncovers a novel crosstalk between two bacterial signaling paradigms namely- c-di-GMP second messenger signaling and Ser/ Thr/ Tyr protein phosphorylation.