Genetic and hysteretic switch behavior determine small colony variant phenotypes in Pseudomonas aeruginosa

Pseudomonas aeruginosa is an important opportunistic pathogen and a major cause of severe acute and chronic infections. P. aeruginosa small colony variants (SCVs) as well as mucoid, alginate-overproducing isolates are frequently isolated from the lungs of patients suffering from cystic fibrosis. In an attempt to uncover the genetic basis underlying the evolution of these highly adapted bacterial phenotypes, we characterized a mucoid clinical SCV in more detail. While the SCV colony morphology was shown to be linked to signaling via the Gac/Rsm signaling system, the elevated c-di-GMP levels was the result of a hysteretic behavior. Our observation of an induced memory response to the conditions that have been encountered during the infection process in the human host seems to be an additional important yet understudied molecular mechanism underlying phenotypic switching. Our finding that both, the hysteretic c-di-GMP-dependent signaling as well as the genetic switching of Gac/Rsm activity, drive overlapping phenotypes in many clinical isolates underline the importance of a tight control of bacterial adaptation to the conditions encountered during an infection process.