Inter-kingdom communication and phenotypic heterogeneity of Legionella in phagocytes

通过小信号分子的种内和种间交流在细菌中很常见，但也用于细菌和真核生物之间的跨王国交流。嗜肺军团菌利用α-羟基酮化合物LAI-1(“军团菌自身诱导物-1”)进行细胞间通讯。嗜肺性乳杆菌在阿米巴和巨噬细胞中建立一个复制空泡，其中细菌从致病的、传播的形式切换到复制的、非移动的形式。在对新型抗毒力化合物的筛选中，我们确定了肾上腺素能信号的拮抗剂，这些拮抗剂可以抑制嗜肺乳杆菌在阿米巴中的细胞内复制。这一发现表明，细菌和/或阿米巴通过儿茶酚胺对肾上腺素能信号转导产生反应。相应地，嗜肺乳杆菌含有QseBC的同系物，QseBC是一个双组分的传感器激酶/反应调节系统，它介导不同的病原菌对肾上腺素能宿主信号的反应。这项应用的目的是详细分析嗜肺乳杆菌和吞噬细胞之间由小信号分子介导的跨王国通讯。为此，我们将使用药理学、生化、遗传学和细胞微生物方法，以及定量建模。将具体讨论以下主题：(I)肾上腺素能信号和QseBC双组分系统在嗜肺乳杆菌王国间通讯和细胞内复制中的作用，以及(Ii)嗜肺乳杆菌对小信号分子反应的表型异质性。

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.