Inter-kingdom communication and phenotypic heterogeneity of Legionella in phagocytes

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Intra- and inter-species communication through small signaling molecules is common among bacteria, but also employed for inter-kingdom communication between bacteria and eukaryotes. The opportun-istic pathogen Legionella pneumophila employs the α-hydroxyketone compound LAI-1 (”Legionella autoinducer-1”) for cell-cell communication. L. pneumophila establishes in amoeba and macrophages a replication vacuole, wherein the bacteria switch from a virulent, transmissive form to a replicative, non-motile form. In a screen for novel anti-virulence compounds we identified antagonists of adrener-gic signaling that inhibit intracellular replication of L. pneumophila in amoeba. This finding suggests that the bacteria and/ or the amoeba respond to adrenergic signal transduction through catechola-mines. Accordingly, L. pneumophila harbors a homologue of QseBC, a two-component sensor kinase/ response regulator system, which mediates the response of different pathogenic bacteria to adrener-gic host signals. The aim of this application is a detailed analysis of inter-kingdom communication mediated by small signaling molecules between L. pneumophila and phagocytes. To this end, we will use pharmacological, biochemical, genetic and cellular microbial approaches, as well as quantitative modeling. The following topics will be specifically addressed: (i) the role of adrenergic signaling and the QseBC two-component system in inter-kingdom communication and intracellular replication of L. pneumophila, and (ii) the phenotypic heterogeneity in the response of extra- and intracellular L. pneu-mophila to small signaling molecules.