Laureats

Résumé:

Platelets are small blood cells that help stop bleeding by forming clots, but they can also cause life-threatening, clots that stop blood flow to tissues and organs leading to heart attacks or strokes. Most current anti-platelet drugs reduce clotting, but also increase the risk of bleeding, which is a major problem.

In this project, researchers present a new strategy to prevent harmful clot formation without severely affecting clotting. They developed innovative bispecific antibody molecules called cis-acting platelet receptor inhibitors (CAPRIs) that work by limiting specific platelet activation signals rather than completely blocking these critical pathways. CAPRIs bring together a natural inhibitory receptor on platelets (G6B) with activating receptors that are responsible for thrombus formation, including the collagen and immunoglobulin receptors GPVI and FcgRIIA (CD32A), respectively.

By doing this, CAPRIs effectively prevented platelet activation caused by collagen or immune complexes in several disease-related models, including arterial thrombosis, heparin- and vaccine-induced thrombocytopenia (reduced platelet count) and thrombosis (HIT and VITT), antiphospholipid syndrome (APS), and sepsis. Importantly, these effects were seen under conditions that closely mimic blood flow in arteries.

Overall, this research reveals that CAPRIs can selectively block harmful platelet activation pathways. This approach could lead to a new class of anti-thrombotic treatments that are effective at preventing pathological blood clotting while potentially causing fewer bleeding side-effects than current therapeutics.

Projet inter-institut IM2B - ICI

Résumé:

Hunting for Our Microbial Ancestors—The Asgard Archaea

Why Study Asgard Archaea?

Asgard archaea are a group of microbes discovered less than a decade ago, named after Norse gods (Loki, Thor, Odin, Heimdall) because their discovery revolutionized our understanding of how complex life evolved. These microbes are our closest known relatives among the archaea, and they carry genes usually found only in eukaryotes—organisms with complex cells, such as animals, plants, and fungi. It suggests that Asgard archaea might be the living descendants of the ancient microbes that gave rise to all complex life on Earth.

What Do We Know So Far?

Only two Asgard species have been grown in the lab, respectively by a Japanese and an Austrian team: ‘Candidatus Prometheoarchaeum syntrophicum’ lives in partnership with other microbes, forms long cellular extensions, and may have played a key role in the origin of eukaryotes (Imashi et al., 2020).   ‘Candidatus Lokiarchaeum ossiferum’: Thrives at 20°C, has a larger genome, and shows complex internal structures, possibly thanks to a primitive cytoskeleton (Rodrigues-Oliveira et al. 2023). These findings support the idea that eukaryotes may have emerged from a fusion between an Asgard archaeon and a bacterium over 2 billion years ago.

Our Project: Cultivating Heimdallarchaeota, Our Closest Microbial Relatives

Microbiologists at the MIO (MEB team) lab have successfully enriched cultures of Heimdallarchaeota—the Asgard group most closely related to eukaryotes—from hydrothermally heated sediments. These microbes live in extreme conditions (45–55°C, acidic, oxygen-free). Scientists used in situ microbial culture devices to enrich Asgard archaea. Back in the lab, they could maintain the growth of these microbes under controlled conditions. Yet Heimdall archaea represent a tiny fraction of the microbial cultures. Still, their cells could be visualized by specific microscopy techniques (FISH-confocal microscopy) at the BIAM lab, thanks to collaboration with researchers of the BEAMM team.

Our Goals in the Asgardomics project:

1) Obtain the first stable culture of Heimdallarchaeota to study their cell structure and metabolism.

2) Understand how these microbes might have given rise to eukaryotes.

3) Test hypotheses about the evolution of complex life.

To achieve these objectives:

We will use innovative and complementary Methods

-  Dedicated culture methods, including novel in situ enrichments and middle-throughput techniques

- Deep sequencing of enrichment cultures (metagenomics) for bioinformatic reconstruction of Asgard archaea genomes, which will help us decipher their metabolism and lifestyle and shed light on the evolutionary relationship with other archaea and eukaryotes.

-  Advanced microscopy to visualize cell structures, like the primitive cytoskeleton.

Challenges and Stakes

Challenge: These microbes are a minority in their natural ecosystem, grow very slowly, and are fragile.

Originality: No one has yet succeeded in cultivating Heimdallarchaeota.

Potential: A stable culture could unlock mysteries about the origin of eukaryotes

What’s Next?

If successful, these archaea could become a global research model, attracting international collaborations and opening new avenues for understanding the evolution of early eukaryotic life.

Résumé:

Le projet HET-FLOW a pour objectif de développer des outils de biologie cellulaire à haute résolution faisant intervenir la cytométrie en flux afin de détecter simultanément, dans une même cellule, des transcrits et des protéines, et éventuellement d’autres caractéristiques fonctionnelles telles que le potentiel de membrane.

Nous utiliserons le modèle Lactococcus cremoris, une bactérie fermentaire possédant néanmoins des éléments de chaîne respiratoire, dont un, le cytochrome bd, présente une hétérogénéité de production d’une cellule à l’autre dans certaines conditions environnementales. Afin de déterminer si cette hétérogénéité protéique est liée à une hétérogénéité au niveau transcriptionnelle, nous transposerons la méthode de flow-FISH déjà établie pour les cellules eucaryotes au cellules bactériennes. Nous utiliserons également des marqueurs fluorescents du potentiel de membrane afin de déterminer si l’hétérogénéité de production de protéines se traduit par une hétérogénéité fonctionnelle, testant la capacité respiratoire des cellules. La finalité sera de corréler production de protéine, expression des gènes et fonctionnalité de la chaine respiratoire au niveau de la cellule unique.

Une fois mis au point sur la question relative à notre modèle, les outils développés seront destinés à être mis à disposition de la communauté des microbiologistes afin notamment de permettre l’étude de la variabilité phénotypique et des stratégies d’adaptation bactérienne.

The genus Neisseria provides an especially informative model for understanding how evolution reshapes bacterial “lifestyles”. Within the same genus, some species are primarily commensal, whereas others are pathogens capable of causing infection. The project starts from a simple idea: before a bacterium can become pathogenic, it must first pass through key steps such as adapting to a new environmental niche. Moving from one environment to another (for example, from the oral cavity to the nasopharynx, or from one colonization site to another) exposes bacteria to new chemical constraints and immune pressures.

At the core of the study are two selective pressures. The first is copper homeostasis: copper is essential at low levels but becomes toxic when in excess. The second is redox stress (oxidative and nitrosative), often linked to host defense mechanisms, which can damage proteins and disrupt metabolism. The project investigates the hypothesis that, over the course of Neisseria evolution, these two responses have been “rewired”. Instead of being controlled by the canonical copper regulator CueR, the expression of key copper-export genes may have shifted under the control of NmlR, a regulator associated with the redox stress response. Such a reorganization would more tightly couple copper detoxification with resistance to oxidative stress potentially providing an advantage during niche transitions and, indirectly, affecting the ability to cause disease.

To test this hypothesis, we will compare many Neisseria species, experimentally characterize how CueR and NmlR function, and then swap regulatory modules between species to assess causally the impact on copper tolerance, redox-stress resistance, and survival in the presence of immune cells. The ultimate goal is to determine whether certain traits associated with pathogenesis primarily reflect ecological adaptation to new niches, rather than an intrinsic link to virulence.

In photosynthetic organisms, light absorption is essential for growth. Absorbed in excess however, it leads to cell damage. These organisms have thus developed a large array of photoprotective mechanisms, most of which target light-harvesting antennae. In plants, the main antenna is the Light-Harvesting Complex II (LHCII), a trimer of membrane, pigment-binding proteins, which is thus at the heart of the critical trade-off between light harvesting and photoprotection. There is a long-standing debate over the triggers of photoprotection and their effect on LHCII’s switch between light-harvesting and energy dissipative states. Yet, understanding this switch and its regulation is of major importance for fields ranging from crop stress resilience to reduction of energy loss in biotechnological applications.

This project aims to investigate which light acclimation-induced changes on the plant light-harvesting complex regulate its ability to cluster and / or interact with other complexes, and thus to modulate light capture and energy dissipation.

Our preliminary research has indeed evidenced a change in clustering properties of LHCII between complexes purified from dark- and light-adapted plants. Yet, an array of modifications on LHCII or its immediate surroundings, well-known (carotenoids) or little explored (lipids, surface charges modifications) can explain the change. Using biochemistry, fluorescence spectroscopy, and to some extent genetics and structural biology, we are now investigating if each of these parameters influences LHCII interacting properties – and how!

Some microorganisms can use electricity in much the same way humans use food: as a source of energy. Some of them are even able to take electrons directly from an electrode and use this energy to transform carbon dioxide (CO₂) into useful molecules. This process, called microbial electrosynthesis, is a promising technology for producing sustainable fuels, chemicals, and materials from renewable electricity while recycling CO₂. However, current systems rely on a very limited number of known microorganisms, which strongly restricts what can be produced and under which conditions.

This project aims to unlock a largely unexplored biological resource: polyextremophilic microorganisms. These microbes live in extreme environments such as high temperature, high salinity, or extreme pH, for example in deep-sea hydrothermal vents. Recent research suggests that such organisms could greatly expand the range of molecules that can be produced by microbial electrosynthesis, and operate under conditions where conventional microbes fail.

To achieve this, the project develops a new generation of low-cost, miniaturized, and automated electrosynthesis reactors using 3D printing and open-source electronics. Unlike existing systems that are very expensive and scarce, these devices make it possible to rapidly test many extreme conditions in parallel. Hydrothermal vent samples collected during oceanographic campaigns will be enriched, screened, and analyzed to identify new electricity-using microorganisms and microbial communities.

Ultimately, the project seeks to isolate new strains capable of converting CO₂ and electricity into valuable products such as bioplastics, organic acids, alcohols, or energy carriers. Beyond its biotechnological potential, this work will open a new field of research at the intersection of microbiology, electrochemistry, and extreme environments, with implications for sustainable industry, deep-sea ecology, and even future space exploration.

Iron-sulfur (Fe-S) clusters are essential prosthetic groups involved in a myriad of cellular processes, including respiration, DNA repair, and immune defense. The biogenesis of Fe-S clusters is tightly regulated, with, in the model organism Escherichia coli, two Fe-S biogenesis machineries - ISC and SUF - operating under different conditions. While ISC ensures Fe-S cluster maturation under standard growth conditions, the less efficient SUF machinery intervenes during stress conditions like reactive oxygen species or iron limitation. This switch has significant physiological consequences, such as increased tolerance to certain antibiotics.

Recent studies have highlighted the critical role of small regulatory RNAs (sRNAs) in bacterial responses to stress, for example, in the activation of the SUF machinery under oxidative stress and iron starvation. Strikingly, recently published interactome datasets support a much larger post-transcriptional regulatory network centered around the ISC and SUF machineries.

This project aims to uncover a potential broader role for sRNAs in regulating Fe-S cluster biogenesis across diverse environmental conditions, beyond the well-established triggers like oxidative stress or iron limitation. Through bioinformatic analyses and experimental validation, the first objective is to identify novel interactions between sRNAs and mRNAs involved in Fe-S cluster biogenesis. By focusing on a selection of the most relevant regulatory interactions, mechanisms of action will be further investigated both in vitro and in vivo. Finally, the physiological impact of these regulations on bacterial adaptation to various stress conditions will be explored.

By unveiling this intricate regulatory network, this project will advance our understanding of Fe-S cluster biogenesis and shed light on the remarkable adaptability of bacteria to diverse environmental challenges.

This project aims to advance the understanding of antimicrobial peptides (AMPs) and their molecular interactions with cells. AMPs are key components of innate immunity and display broad biological activities, including antimicrobial and anticancer effects, making them promising candidates for innovative therapeutic strategies. The research focuses on temporins, a family of peptides originally identified in frog skin, whose precise molecular targets remain largely unknown. By combining chemical biology approaches with advanced analytical methods, the project seeks to identify and validate the cellular interaction partners of selected temporin peptides in microorganisms and cancer cells. This work strengthens knowledge at the interface of chemistry and biology and supports the development of next-generation bioactive molecules with potential biomedical applications.

Understanding how plants resist environmental stresses such as drought and high temperatures is essential as these factors severely limit global plant growth and biomass production. Plants adapt to changing environments through finely tuned cellular responses, with guard cells playing a central role. These cells regulate the opening and closing of stomata (pores on leaf surfaces), controlling the exchange of CO₂ and water vapor, and thus directly influencing photosynthesis, water use efficiency, and biomass production.

Guard cells integrate multiple signals (humidity, temperature, CO₂ levels) and adjust stomatal movements by regulating ion fluxes across their membranes. Mechanosensitive ion channels that respond to mechanical forces are known to act as sensors in many organisms, rapidly converting physical stress into ionic signals. In plants, four families of mechanosensitive channels (MSL, MCA, PIEZO, OSCA) have been identified, but their specific roles in guard cell function remain largely unexplored.

This project aims to identify which channels are active in guard cells and characterize their function using gene expression analysis, mutant studies, and advanced electrophysiological techniques. By linking channel activity to stomatal behavior, the research seeks to uncover new molecular targets for improving crop resilience under stress.

Microbial bioprocess scale-up for the production of molecular energy vectors is currently facing major challenges to reach competitive productivity levels, resulting in poor cost and sustainability performances despite encouraging results at laboratory scale. Microalgae bioprocesses for instance is limited at larger scale by light availability and gaseous substrates delivery. In parallel, the chemical industry, likewise aiming to increase performance and sustainability, has embarked in a green revolution leading to the process intensification conceptual framework. An important achievement from process intensification research has been the development of continuous microreactors enabling major performance improvements in terms of gas transfer, heat transfer, and mixing performance. In addition, the modularity of microreactors provides an opportunity for rapid scale-up from prototypes in stark contrast to the scale-up of classical discontinuous batch reactors.

We propose for this project to build on results from process intensification research, and take advantage of the skillset of the project coordinator in microalgae processes, to develop a microphotobioreactor for the intensified cultivation of microalgae. The microphotobioreactor will be designed and tested for the optimisation of gas transfer and light distribution with the help of the research team PROMETHEE in M2P2 specialised in process intensification at microscale. Having validated the microreactor design, initial cultivation tests will be performed with a strain of Chlorella vulgaris for which lipid productivity was previously characterized and modelled in a previous study by the project coordinator. This work will provide a first verification of the microreactor intensification potential. Finally, our set-up will be tested for microalgal phototrophic dihydrogen production by maintaining anoxic conditions under light illumination which we hypothesise will be permitted by the intensified gas stripping performance of the newly designed microreactor.

The proposed project will be a stepping stone for the M2P2 laboratories in the development of 1) microalgal cultivation skillset and 2) opening a new research line on bioprocess intensification which we aim to extend to other metabolisms in the future.