Katharios-Lanwermeyer, S.; Zarrella, T. M.; Godsil, M.; Severin, S.; Casiano, A. E.; Tai, C.-H.; Khare, A.

Microorganisms commonly exist in polymicrobial communities, where organisms can respond to interspecies secreted molecules by altering behaviors and physiology, however, the underlying mechanisms remain underexplored. Here we investigated interactions between Stenotrophomonas maltophilia and Pseudomonas aeruginosa, co-infecting opportunistic pathogens found in pneumonia and chronic lung infections, including in cystic fibrosis. We found that S. maltophilia forms robust protective multicellular aggregates upon exposure to P. aeruginosa secreted factors. Experimental evolution for lack of aggregation selected for fimbrial mutations and we found that fimbriae are required on both interacting S. maltophilia cells for aggregation. Untargeted metabolomics and targeted validations revealed that the quorum sensing molecule Pseudomonas quinolone signal (PQS) directly induced S. maltophilia aggregation, and co-localized with the aggregates. Further, in co-culture with P. aeruginosa, wild-type S. maltophilia formed aggregates, resulting in up to 75-fold increased survival from P. aeruginosa competition compared to fimbrial mutants. Finally, multiple other bacterial species similarly aggregated upon exposure to P. aeruginosa exoproducts, indicating a more general response. Collectively, our work identifies a novel multispecies interaction where a quorum sensing molecule from a co-infecting pathogen is sensed as a \"danger\" signal, thereby inducing a protective multicellular response.