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Unmasking the spatial code - How global and local c-di-GMP signaling modules regulate bacterial behavior and virulence

Research Project
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01.04.2022
 - 31.03.2026

The concentration of bacteria on surfaces (including animals and plants) is orders of magnitudes higher than in the surrounding environment, offering bacteria ample opportunity for mutualistic, symbiotic, and pathogenic interactions. To efficiently populate surfaces, bacteria have evolved mechanisms to sense mechanical or chemical cues upon contact with solid substrata. This is of particular importance for pathogens that interact with host tissue surfaces as they need to rapidly adapt to this environment to optimize adherence, tissue dissemination and virulence. Recent work has revealed that small signaling molecules like c-di-GMP and cAMP play key roles in this process, but the mechanisms by which these molecules instruct bacteria on surfaces have remained largely unchallenged. Moreover, experimental systems that allow scrutinizing mechanisms and processes involved in tissue colonization by important pathogens under realistic, human-like conditions are missing. Here, we propose to dissect the role of c-di-GMP in surface colonization of Pseudomonas aeruginosa , an opportunistic human pathogen that is able to invade the human host by effectively colonizing mucosal surfaces. Our studies will probe the initial stages of this process including surface attachment, virulence induction and surface motility to better understand the powerful invasion and dissemination strategies of this pathogen. We will investigate these processes on abiotic surfaces and on human lung organoids to be able to challenge the relevance of in vitro studies. We will explore how c-di-GMP signaling is coordinated with cAMP and how these signaling molecules regulate P. aeruginosa surface colonization with high precision and specificity. Our studies will focus on two c-di-GMP binding proteins, FimW and FimX, which regulate type IV pili, a prime virulence factor, to drive distinct and antagonistic processes, surface adherence and twitching motility. To dissect the dynamic regulation of these processes, we will develop powerful biosensors that allow monitoring changes of c-di-GMP and cAMP in real time and with high temporal and spatial resolution. Together with state-of-the-art imaging and powerful genetic analyses of the FimW and FimX pathways, this will uncover distinct second messenger signaling modes operating either on the global level or in local, spatially confined modules, thereby providing unprecedented insight into how P. aeruginosa colonizes tissue surfaces. Studies with P. aeruginosa will be complemented and instructed by investigations of c-di-GMP signaling in two powerful model organisms, Caulobacter crescentus and Escherichia coli . We propose to investigate mechanisms responsible for local c-di-GMP-dependent cell polarity and rapid surface attachment of C. crescentus . As processes involved in Caulobacter surface colonization are strikingly similar to those in P. aeruginosa , these studies will serve as a blueprint for our work with the human pathogen. Studies in E. coli are geared towards a detailed understanding of a newly discovered surface glycan, NGR, which serves as receptor for several bacteriophages. NGR biogenesis and secretion was proposed to be regulated by a local pool of c-di-GMP in a highly specific manner. These studies will provide a detailed understanding of how c-di-GMP controls bacterial processes within confined 'microcompartments' and thus will greatly influence our work with P. aeruginosa both on the conceptual and the experimental level.

Funding

Unmasking the spatial code - How global and local c-di-GMP signaling modules regulate bacterial behavior and virulence

SNF Projekt (GrantsTool), 04.2022-03.2026 (48)
PI : Jenal, Urs.

Members (1)

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Urs Jenal

Principal Investigator