Periodic Reporting for period 5 - MORPHEUS (Deciphering Bacteria-induced Morphogenesis and Protection in marine Eukaryotes)
Reporting period: 2024-04-01 to 2024-10-31
Since the emergence of eukaryotic life in a world already dominated by bacteria, these two domains of life have engaged in a complex interplay of both cooperation and competition. A striking example of this interaction is the phenomenon of bacteria-triggered recruitment and morphogenesis in marine animals — a highly specialized form of cross-kingdom communication. In this remarkable process, bacterial signals drive the radical transformation of simple, free-swimming larvae into fully developed adult organisms.
Bacteria-induced recruitment and morphogenesis play a crucial role in shaping marine ecosystems. For instance, they directly contribute to the formation and maintenance of coral reefs and promote the colonization of submerged surfaces by encrusting organisms. While these bacterial cues are essential for sustaining healthy marine habitats, they are also the primary drivers of biofouling — the accumulation of marine life on artificial structures such as ship hulls — leading to significant economic losses due to increased drag, corrosion, and the need for costly maintenance and cleaning.
Despite its profound ecological and economic significance, the molecular and cellular mechanisms by which bacteria induce these developmental processes remain largely unknown. The ERC-funded project MORPHEUS seeks to close this critical knowledge gap by investigating the chemical and biomolecular foundations of bacteria-driven morphogenesis in emerging marine model organisms, with a particular focus on Hydractinia, a well-established system in cell biology. The project aims to illuminate the marine microbiome associated with Hydractinia, exploring its biosynthetic potential and the chemical nature of the bacterial signals it secretes. By uncovering how these signals orchestrate complex developmental transformations in Hydractinia and related marine eukaryotes, MORPHEUS ultimately strives to advance our understanding of cross-kingdom communication in marine environments.
Bacteria-induced recruitment and morphogenesis play a crucial role in shaping marine ecosystems. For instance, they directly contribute to the formation and maintenance of coral reefs and promote the colonization of submerged surfaces by encrusting organisms. While these bacterial cues are essential for sustaining healthy marine habitats, they are also the primary drivers of biofouling — the accumulation of marine life on artificial structures such as ship hulls — leading to significant economic losses due to increased drag, corrosion, and the need for costly maintenance and cleaning.
Despite its profound ecological and economic significance, the molecular and cellular mechanisms by which bacteria induce these developmental processes remain largely unknown. The ERC-funded project MORPHEUS seeks to close this critical knowledge gap by investigating the chemical and biomolecular foundations of bacteria-driven morphogenesis in emerging marine model organisms, with a particular focus on Hydractinia, a well-established system in cell biology. The project aims to illuminate the marine microbiome associated with Hydractinia, exploring its biosynthetic potential and the chemical nature of the bacterial signals it secretes. By uncovering how these signals orchestrate complex developmental transformations in Hydractinia and related marine eukaryotes, MORPHEUS ultimately strives to advance our understanding of cross-kingdom communication in marine environments.
As part of this project, we successfully established marine aquaculture systems for Hydractinia and related species, and isolated representative symbiotic bacteria capable of inducing morphogenesis in competent Hydractinia larvae as well as in other marine eukaryotes. Hydractinia specimens were collected during seasonal field expeditions from multiple stations worldwide, enabling us to monitor seasonal and location-specific effects on their associated microbiomes.
Employing state-of-the-art sequencing technologies, we conducted whole-genome sequencing on a diverse set of unique bacterial and fungal isolates to support their genetic characterization and manipulation. Chemical analyses of these bacterial species, performed using advanced metabolomic techniques, uncovered several morphogenic signaling molecules associated with bacterial outer membranes or biofilm matrices, which are detected by competent larvae. Notably, we found that these morphogens act synergistically, eliciting a stronger morphogenic response than individual compounds or axenic bacterial biofilms alone. Furthermore, we demonstrated that outer membrane vesicles (OMVs) represent an exceptionally effective delivery mechanism for these bacterial signals.
Through genome-mining strategies, we also identified novel antimicrobial compounds from both aerobic and anaerobic bacterial and fungal species associated with Hydractinia. These include globally abundant bacteria-derived aminolipids with antimicrobial activity, sphingolipids, and in particular bacterial sulfonosphingolipids, which function as crucial inter- and intracellular signaling molecules. In addition, we discovered complex sphingosine-derived natural products that act as selective enzyme inhibitors. Using total synthesis approaches, we developed chemical probes based on these natural products, enabling protein profiling experiments to identify their putative protein targets.
Microbial profiling further provided the first detailed insights into the beneficial microbiome of Hydractinia, allowing us to explore its biosynthetic potential in depth. These studies not only revealed the composition of the microbiome in relation to biotic factors but also elucidated its catabolic and anabolic capacities, offering valuable perspectives on protective and nutritional symbiotic relationships. Moreover, we identified bacterial endosymbionts unique to this system and explored their potential contributions to the health and resilience of the eukaryotic host.
Overall, our work has provided unprecedented molecular insights into the cross-kingdom communication strategies and cellular mechanisms underlying bacteria-induced morphogenesis and host protection in the marine invertebrate Hydractinia and related species.
Employing state-of-the-art sequencing technologies, we conducted whole-genome sequencing on a diverse set of unique bacterial and fungal isolates to support their genetic characterization and manipulation. Chemical analyses of these bacterial species, performed using advanced metabolomic techniques, uncovered several morphogenic signaling molecules associated with bacterial outer membranes or biofilm matrices, which are detected by competent larvae. Notably, we found that these morphogens act synergistically, eliciting a stronger morphogenic response than individual compounds or axenic bacterial biofilms alone. Furthermore, we demonstrated that outer membrane vesicles (OMVs) represent an exceptionally effective delivery mechanism for these bacterial signals.
Through genome-mining strategies, we also identified novel antimicrobial compounds from both aerobic and anaerobic bacterial and fungal species associated with Hydractinia. These include globally abundant bacteria-derived aminolipids with antimicrobial activity, sphingolipids, and in particular bacterial sulfonosphingolipids, which function as crucial inter- and intracellular signaling molecules. In addition, we discovered complex sphingosine-derived natural products that act as selective enzyme inhibitors. Using total synthesis approaches, we developed chemical probes based on these natural products, enabling protein profiling experiments to identify their putative protein targets.
Microbial profiling further provided the first detailed insights into the beneficial microbiome of Hydractinia, allowing us to explore its biosynthetic potential in depth. These studies not only revealed the composition of the microbiome in relation to biotic factors but also elucidated its catabolic and anabolic capacities, offering valuable perspectives on protective and nutritional symbiotic relationships. Moreover, we identified bacterial endosymbionts unique to this system and explored their potential contributions to the health and resilience of the eukaryotic host.
Overall, our work has provided unprecedented molecular insights into the cross-kingdom communication strategies and cellular mechanisms underlying bacteria-induced morphogenesis and host protection in the marine invertebrate Hydractinia and related species.
The MORPHEUS project has resolved a long-standing scientific question by identifying the morphogenic cue responsible for inducing larval settlement in Hydractinia, a challenge that had remained unanswered for over a decade. This achievement was made possible through a pioneering combination of multi-omics approaches, state-of-the-art analytical techniques, and bioactivity-guided assays to investigate bacterial morphogenesis.
Identifying morphogenic signaling molecules posed significant challenges due to their typically low abundance, synergistic bioactivities, and the need for stable, reproducible bioassays to verify their phenotypic effects. Nonetheless, MORPHEUS demonstrated for the first time the widespread presence of these morphogenic signals within bacterial lineages associated with Hydractinia.
Extensive field studies were conducted to monitor the microbiome of Hydractinia and its surrounding environment under varying biotic and abiotic conditions. These efforts enabled the tracing of the origins and distributions of bacterial taxa capable of inducing morphogenesis, and provided insights into the seasonal dynamics of the microbial communities.
The project also advanced the isolation and synthetic reproduction of highly bioactive compounds that either induce morphogenesis or offer protective functions to their bacterial producers and the Hydractinia hosts. These molecules represent promising candidates for future pharmaceutical development with potential benefits for human health.
Further, the project explored the complex mode of action of these morphogenic compounds, recognizing that the organismal response involves not only the initial receptor recognition but also intricate downstream signaling pathways with both positive and negative feedback loops. By integrating structural data with an omics-based analytical framework, MORPHEUS mapped critical steps within these cellular signaling cascades.
In conclusion, the MORPHEUS project has significantly advanced our understanding of the diversity, bioactivity, and perception mechanisms of a wide range of morphogens, while elucidating their biosynthetic pathways. This knowledge has already been applied to manipulate model systems, providing valuable insights into structure–activity relationships and the evolutionary history of these signals. These results pave the way for future drug discovery programs and will support research on how rising global temperatures may disrupt the microbiomes and life cycles of marine invertebrates like Hydractinia, with potential consequences for their survival in a changing climate.
Identifying morphogenic signaling molecules posed significant challenges due to their typically low abundance, synergistic bioactivities, and the need for stable, reproducible bioassays to verify their phenotypic effects. Nonetheless, MORPHEUS demonstrated for the first time the widespread presence of these morphogenic signals within bacterial lineages associated with Hydractinia.
Extensive field studies were conducted to monitor the microbiome of Hydractinia and its surrounding environment under varying biotic and abiotic conditions. These efforts enabled the tracing of the origins and distributions of bacterial taxa capable of inducing morphogenesis, and provided insights into the seasonal dynamics of the microbial communities.
The project also advanced the isolation and synthetic reproduction of highly bioactive compounds that either induce morphogenesis or offer protective functions to their bacterial producers and the Hydractinia hosts. These molecules represent promising candidates for future pharmaceutical development with potential benefits for human health.
Further, the project explored the complex mode of action of these morphogenic compounds, recognizing that the organismal response involves not only the initial receptor recognition but also intricate downstream signaling pathways with both positive and negative feedback loops. By integrating structural data with an omics-based analytical framework, MORPHEUS mapped critical steps within these cellular signaling cascades.
In conclusion, the MORPHEUS project has significantly advanced our understanding of the diversity, bioactivity, and perception mechanisms of a wide range of morphogens, while elucidating their biosynthetic pathways. This knowledge has already been applied to manipulate model systems, providing valuable insights into structure–activity relationships and the evolutionary history of these signals. These results pave the way for future drug discovery programs and will support research on how rising global temperatures may disrupt the microbiomes and life cycles of marine invertebrates like Hydractinia, with potential consequences for their survival in a changing climate.