Functional characterization of the pH-sensing ArsRS two-component system of Helicobacter pylori and of its regulon

幽门螺杆菌是引起慢性B型胃炎和胃或十二指肠溃疡的病原体。此外，幽门螺杆菌感染与胃腺癌和MALT淋巴瘤的发生有关。嗜中性细菌幽门螺杆菌应对胃腔的极端酸性pH的能力对于其生态位的成功定植是不可或缺的。依赖于pH的基因调控，包括控制必要的定植因子尿素酶的表达，是由ArsRS双组分系统通过低pH触发的磷酸继电器介导的。然而，观察到arsR是一个必需基因，而arsS不是，这表明存在其他不受pH调节的靶基因，但需要非磷酸化的反应调节因子arsR来进行转录调控。本方案的目的是通过鉴定完整的ArsR依赖调节子来表征ArsRS酸反应系统和非磷酸化ArsR的作用。此外，还将详细研究组氨酸激酶ArsS的周质输入结构域对pH敏感的机制，并将其与蛋白细菌相关非胃成员的同源传感器蛋白进行功能比较。

The human gastric pathogen Helicobacter pylori is the causative agent of chronic type B gastritis and gastric or duodenal ulcer disease. Moreover, infection with H. pylori is known to be associated with the development of gastric adenocarcinoma and MALT lymphoma. The ability of the neutralophilic bacterium H. pylori to cope with the extremely acidic pH of the stomach lumen is indispensable for the successful colonization of its niche. pH-dependent gene regulation including the control of expression of the essential colonization factor urease is mediated by the ArsRS two-component system via a phosphorelay which is triggered by low pH. However, the observation that arsR is an essential gene, while arsS is not, indicates that additional target genes exist which are not pH-regulated but require the unphosphorylated response regulator ArsR for their transcriptional control. The aim of the present proposal is the characterization of the ArsRS acid response system and the role of unphosphorylated ArsR by the identification of the complete ArsR-dependent regulon. Furthermore, the mechanism of pH-sensing by the periplasmic input domain of the histidine kinase ArsS will be investigated in detail and a functional comparison with the orthologous sensor proteins of related non-gastric members of the ¿-proteobacteria will be performed.