Inter-kingdom communication and phenotypic heterogeneity of Legionella in phagocytes

吞噬细胞中军团菌的界间通讯和表型异质性

• 批准号: 218310536
• 负责人: Professor Dr. Hubert Hilbi
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/218310536?language=en
• 关键词: Inter; kingdom; communication; phenotypic; heterogeneity

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.

通过小信号分子进行种内和种间的通信在细菌中很常见，但也用于细菌和真核生物之间的界间通信。机会性致病菌嗜肺军团菌利用α-羟基酮化合物LAI-1（军团菌自诱导剂-1）进行细胞间通讯。嗜肺乳杆菌在阿米巴原虫和巨噬细胞中形成一个复制液泡，其中细菌从毒性的、传播的形式转变为复制的、非运动的形式。在筛选新的抗毒化合物中，我们发现了肾上腺素能信号的拮抗剂，可以抑制阿米巴原虫的嗜肺乳杆菌的细胞内复制。这一发现表明细菌和/或变形虫通过儿茶酚地雷响应肾上腺素能信号转导。因此，嗜肺乳杆菌含有QseBC的同源物，QseBC是一种双组分传感器激酶/反应调节系统，可介导不同致病菌对肾上腺素能性宿主信号的反应。本应用程序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王国间通信。为此，我们将使用药理学，生物化学，遗传和细胞微生物方法，以及定量建模。以下主题将具体讨论：(i)肾上腺素能信号和QseBC双组分系统在嗜肺乳杆菌的界间通信和细胞内复制中的作用，以及（ii）嗜肺乳杆菌胞外和胞内对小信号分子反应的表型异质性。