WP 5.3 Eavesdropping Interdomain Signals and Modulators

project description

Adaptation within multi-species communities is the key to persistence in ever-changing environments and successful colonization of a eukaryotic host. Organisms use chemical signals to coordinate their behavior across cells, tissues, and populations. Although these signals are often exclusively produced to communicate between organisms within a domain, eavesdropping or intercepting these chemical messages could provide important cues for outside members to adaptively respond.

We hypothesize that metabolites and compounds commonly classified as intradomain signals frequently serve as cues to direct and control adaptive responses in other domains. Eukaryotes, bacteria, archaea, fungi, and, to some degree, even viruses may monitor each other’s signaling status to prepare for taking chances in symbiotic interactions or take preemptive measures for impending hostile interactions. Specific metabolites like microbial indole derivatives may be part of a trade between beneficial commensals and their human/animal or plant hosts. Other metabolites may serve as cues to adaptively respond to the host’s nutritional or immune status.

The key questions of this WP therefore are: (i) What types of metabolites (e.g., quorum sensing signals, metallophores, indole derivatives (remove metabolites), etc.) function as interdomain cues? (ii) Which types of responses can be elicited by eavesdropping interdomain signals? (iii) How do eukaryotic hosts differentiate between microbial friends and foes? By addressing these questions, we will be able to identify commonalities and concepts that shape interdomain interactions in microbiomes, with the ultimate goal of exploiting these chemical entities and motifs as modulators for deliberately manipulating interactions in complex microbiomes or host-microbe systems in the second stage of the CoE.

Although individual examples for small molecules mediating interdomain interactions exist, systematic investigations into the chemistry of this form of crosstalk are lacking. We will apply a unique combination of natural product analytics and synthetic chemistry with an extensive breadth of biological analysis tools only found in the highly collaborative CoE setting, including immunological, ecological, and metabolomics methods. In a hypothesis-driven approach, we will produce or partially purify quorum sensing signals (e.g., PQS, AHLs, AI-2, AIPs), indole derivatives and other metabolites from key species of human, soil, and plant microbiomes as well as selected host factors (e.g. , hormones, cytokines). These compounds will be extensively tested using D₂O- and ¹³C-based stable isotope probing combined with SRS-FISH for effects on species composition and activity in intact microbiomes. Metabolites from commensals and pathogenic microbial species will be investigated for their potential to shape immune responses, including, but not limited to, their effects on inflammatory cytokines produced by innate and adaptive immune cell types. We will also investigate the effects of human hormones on microbial secondary metabolite responses by LC-MS using pure cultures and whole microbiomes.

In addition, this WP will profit from synergies within the CoE that will allow us to identify metabolites from interactions detected in other WPs by structure elucidation using 1D and 2D NMR spectroscopy in combination with HR mass spectrometry. This WP will provide a fundamental molecular understanding of interdomain signals and modulators by linking biological activities with the chemical structures of the corresponding metabolites.