We study the role of the second messenger cyclic di-GMP in persistence and chronic infections of bacterial pathogens. Building on our expert knowledge in biochemical, structural, and cellular mechanisms of c-di-GMP signaling, we are establishing two model systems for chronic infections, Pseudomonas aeruginosa and uropathogenic Escherichia coli. During long-term cystic fibrosis lung infections, P. aeruginosa undergoes genetic adaptation resulting in progressively increased persistence and the generation of adaptive colony morphotypes. This includes small colony variants (SCVs), auto-aggregative, hyper-adherent cells whose appearance correlates with poor lung function and persistence of infection. The SCV morphotype is strongly linked to elevated levels of cyclic-di-GMP, a ubiquitous bacterial second messenger that regulates the transition between motile, planktonic and sessile, cooperative lifestyles. The aim of this project is to dissect the c-di-GMP signaling network in P. aeruginosa and to uncover its implication in SCV formation and in vivo persistence.
In parallel, we study persistence mechanisms in uropathogenic E. coli. Recurring urinary tract infections by pathogenic E. coli are a major problem for human health, causing severe morbidity and tremendous costs for the health care system. Recently the underlying source of infection relapses has been linked to biofilm formation in the bladder epithelium. These bacterial communities are metabolically silent and largely insensitive against antibiotics. We have made use of an Escherichia coli in vitro model to identify molecular factors involved in biofilm formation. This has uncovered c-di-GMP as a key regulator in orchestrating the transition of Escherichia coli cells to the quiescent biofilm state by stimulating the production of the polysaccharide adhesin poly-b-1,6-N-acetyl-glucosamine (Pga). The recent implication of Pga in virulence of UPECs has prompted us to address the molecular basis of c-di-GMP mediated Pga stimulation and to investigate the role of Pga regulation in urinary tract infections.