Interkingdom adenosine signal reduces Pseudomonas aeruginosa pathogenicity

Pseudomonas aeruginosa is becoming recognized as an important pathogen in the gastrointestinal (GI) tract. Here we demonstrate that adenosine, derived from hydrolysis of ATP from the eucaryotic host, is a potent interkingdom signal in the GI tract for this pathogen. The addition of adenosine nearly abolished P. aeruginosa biofilm formation and abolished swarming by preventing production of rhamnolipids. Since the adenosine metabolite inosine did not affect biofilm formation and since a mutant unable to metabolize adenosine behaved like the wild-type strain, adenosine metabolism is not required to reduce pathogenicity. Adenosine also reduces production of the virulence factors pyocyanin, elastase, extracellular polysaccharide, siderophores and the Pseudomonas quinolone signal which led to reduced virulence with Caenorhabditis elegans. To provide insights into how adenosine reduces the virulence of P. aeruginosa, a whole-transcriptome analysis was conducted which revealed that adenosine addition represses genes similar to an iron-replete condition; however, adenosine did not directly bind Fur. Therefore, adenosine decreases P. aeruginosa pathogenicity as an interkingdom signal by causing genes related to iron acquisition to be repressed.