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Project A04

Principal Investigator: Prof. Dr. Oliver Werz, Dr. Pierre Stallforth

Chemical Mediators in the Interaction Between Phagocytes and Their Prey

Macrophages (Macs) and amoebae are both exquisite systems to study the combat between phagocytes and bacteria or aberrant mammalian cells. Small molecule mediators play crucial, yet poorly understood roles in the interaction between these phagocytes and their prey. Identifying these signals and understanding their roles in interacting cellular communities can lead to previously inaccessible bioactive molecules and advance the fields of cellular communication. This project will shed light on two related but contextually distinct aspects of chemical signaling during phagocytosis of different preys. The first part (O. Werz) focuses on different human Mac phenotypes (M1, M2) with beneficial (M1) or deleterious functions (M2) towards cancer cells. Macs are major sources of lipid mediators (LM) that display pivotal bioactivities in inflammation and cancer. We study how LM signaling structures monocyte/Mac - cancer cell communities (MMCCC) that co-exist in tumors, and the manipulation by environmental factors (bacteria, androgens) and small molecules. We found that pathogenic bacteria activate M1 and M2 to produce distinct LM with deleterious or beneficial properties, which is influenced by cancer cells. How these LM affect cancer cells and how LM impact the interaction between M1 and M2 with consequences for tumors is still unknown. We will investigate molecular determinants of LM formation and modulation by cancer cells, LM signaling and physiology, as well as modulation of LM biosynthesis by small molecules, environmental factors, and smart/functional surfaces (all provided by the CRC). We will consider the complexity of MMCCC in biochip assays. Finally, we will study if combat of other organisms with pathogenic bacteria induces such LM signaling in relevant communities addressed within the CRC, such as the phagocyte Dictyostelium discoideum (see below) or diatoms/algae when exposed to pathogenic bacteria.

The second part (P. Stallforth) focuses on the aspect of bacterial defense mechanisms against amoebal phagocytes and how chemical mediators enable bacteria to evade phagocytosis. Previous efforts have led to the characterization of novel, bacterially produced, small molecules that enable protection of the producing organism against amoebal phagocytes. Here, we wish to understand bacterial molecular communication mechanisms that lead to the cooperative production of anti-predator toxins in the presence of the amoeba D. discoideum. The system consists of genetically tractable Pseudomonas species and the well-characterized model organism D. discoideum. While each single bacterial species cannot defend itself against the predator, in co-culture the bacteria produce toxins that enable evasion of predation. We will identify the underlying signal molecules. This project requires expertise in differential metabolomics and mass spectrometry imaging as well as pharmacological characterization of small molecules, all of which are available within this CRC. Importantly, the production of any LM of the amoeba D. discoideum upon contact with defensive bacteria is not known, yet the amoebal genome harbors some genes required for LM production. Since many bacterial organisms are sequenced and genetically tractable, bioinformatics and molecular biological approaches for the identification of key biosynthetic genes will be feasible. Within the CRC, we offer expertise regarding the sequenced and genetically tractable eukaryotic model organism D. discoideum, an important macrophage mimic and valuable tool to study phagocytosis, chemotaxis, and host-microbe interactions. Together, our studies will provide novel insights into the role of chemical mediators in phagocyte prey interactions both in a microbial and human context.

 

Team A04

Prof. Dr. Oliver Werz


Chair for Pharmaceutical / Medicinal Chemistry, Institute of Pharmacy

Friedrich Schiller University Jena

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Dr. Pierre Stallforth


Research Group: Chemistry of Microbial Communication

Leibniz Institute for Natural Product Research and Infection Biology – Hans-Knöll-Institute

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Dr. Simona Pace


Institute of Pharmacy

Friedrich Schiller University Jena

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Dr. Andreas Koeberle


Institute of Pharmacy

Friedrich Schiller University Jena

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Shuai-Bing Zhang



Research Group: Chemistry of Microbial Communication
Leibniz Institute for Natural Product Research and Infection Biology – Hans-Knöll-Institute

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