Vibrio cholerae c-diGMP signaling: motile to biofilm transition and transmission

描述（由申请人提供）：霍乱弧菌是霍乱的病原体，是一种重要的人类病原体，是拉丁美洲、亚洲、南美洲和非洲许多发展中国家地区持续存在的公共卫生问题。在包括霍乱弧菌在内的许多细菌中，环状二聚鸟苷一磷酸（c-diGMP）调节运动性、生物膜形成和毒力。我们对c-diGMP周转和c-diGMP依赖性表型的基本生物化学有了坚实的总体了解，但仍存在许多关键问题。这些包括c-diGMP如何机械地控制霍乱弧菌中的能动性到生物膜生活方式的转换，环境信号如何控制霍乱弧菌中的c-di-GMP水平和生物膜形成，以及c-diGMP信号传导在肠道和水生以及霍乱弧菌生命周期的阶段中的后果。我们将围绕两个目标来解决这些问题。在目标1中，我们将确定特定的关键c-diGMP信号蛋白如何控制运动。我们还将分析生物膜发育过程中的c-diGMP产生，并阐明运动状态如何影响c-diGMP水平。在目标2中，我们将确定c-diGMP水平的环境调节的分子机制，并分析c-diGMP信号传导蛋白在霍乱弧菌水生和肠道生命周期中的影响。我们的研究将导致更好地了解c-diGMP信号转导途径，这对霍乱弧菌的生命周期至关重要，因此可能导致对抗这种病原体的新方法，以及使用c-diGMP信号的其他致病微生物。这项工作也将有助于对新出现的、无处不在的信号转导网络的基本理解，因此，也将有助于了解广泛细菌中的类似调控系统。

DESCRIPTION (provided by applicant): Vibrio cholerae, the causative agent of the disease cholera, is an important human pathogen that is an ongoing public health problem in regions of many developing countries in Latin America, Asia, South America and Africa. In many bacteria including V. cholerae, cyclic dimeric guanosine monophosphate (c-diGMP) regulates motility, biofilm formation and virulence. We have a solid general understanding of the basic biochemistry of c-diGMP turnover and c-diGMP- dependent phenotypes, but many critical questions remain. These include how does c-diGMP mechanistically control motile to biofilm life style switch in V. cholerae, how do environmental signals control c-di-GMP levels and biofilm formation in V. cholerae, and what are the consequences of c-diGMP signaling in the intestinal and aquatic and phases of V. cholerae life cycle. We will address these questions by focusing on two aims. In Aim 1, we will determine how specific key c-diGMP signaling proteins act to control motility. We will also analyze c- diGMP production during biofilm development and elucidate how motility status affects c-diGMP levels. In Aim 2, we will determine molecular mechanisms of environmental regulation of c- diGMP levels and analyze impact of c-diGMP signaling proteins in V. cholerae aquatic and intestinal life cycles. Our studies will lead to a better understanding of c-diGMP signal transduction pathways that are critical for the life cycle of V. cholerae and may, therefore, lead to new methods of combating this pathogen, as well as other disease-causing microorganisms that use c-diGMP signaling. This work will also contribute to the basic understanding of the newly emerging, ubiquitous signal transduction network and, therefore, will also be relevant to understand similar regulatory systems in a broad range of bacteria.