IPBS researchers coordinate or are partners in 9 projects funded by the French National Research Agency
The COMETH (ImportanCe of inflammasOmes in eMerging Environmental Toxin-driven patHologies) project, coordinated by Céline Cougoule, addresses significant environmental changes due to global warming, such as emerging pathogens and marine toxins. The algal species Vulcanodinium rugosum, once confined to tropical waters, now inhabits temperate Atlantic and Mediterranean areas, producing the toxic metabolite Portimine. This toxin causes severe skin, eye, and lung inflammation, with over 2,000 cases reported since 2021. Understanding how Portimine impacts human health and the involved molecular mechanisms is crucial. Preliminary results suggest the NLRP1 inflammasome drives Portimine-dependent pathology. Our research aims to 1) decipher how Portimine activates the NLRP1 inflammasome in keratinocytes and airway epithelial cells, 2) examine Portimine-induced pathology in human organoids and zebrafish, and 3) explore the therapeutic potential of NLRP1 inhibition. This study will provide the first evidence of NLRP1’s role in Portimine-induced pathology and offer new therapeutic leads.
The aim of the FOXKONTROL (Regulation of Foxk1 in the Control of T Cell Activation) project, in which Anne Gonzalez de Peredo is a partner, is to characterize a transcription factor called FOXK1, identified as important for the control of T lymphocyte metabolism. T cell functions are closely linked to metabolic programs, and understanding the molecular components regulating these changes is crucial for comprehending T cell immune responses. By combining original mouse models and unbiased global “Omics” approaches, we will assess T cell effector/memory responses in various contexts and analyze how FOXK1 controls gene and protein expression during T cell activation. We aim to gain insight into this key metabolic player, opening new directions for therapies involving T cells.
The 56-epoxycholestanols form dendrogenins A, B, and C by conjugation with histamine, spermidine, or glutathione, respectively. Dendrogenin A has been identified as a modulator of the nuclear receptor LXR, regulating cell differentiation and immunity. This project, DASYNT3 (Further Exploration of the Epoxycholestanol Metabolic Pathway), involving Laurent Maveyraud as a partner, aims to gain a better understanding of the reaction mechanisms of the glutathione S-transferases responsible for the biosynthesis of dendrogenins and to define the effects of these compounds on the structure and function of LXR.
The aim of the proposal DynamOC (Understanding the Dynamics of Osteoclasts in Growth and Ageing), involving Christel Vérollet and Frédéric Lagarrigue as partners, is to decipher the phenotypic and functional diversity of bone-resorbing osteoclasts in growth and ageing, and establish a landscape of osteoclasts throughout life to understand how the different osteoclast populations evolve in association with the bone marrow environment. This will provide novel information that will help us understand how these changes contribute to the development of bone pathologies such as osteoporosis.
The project SpaCELLM (Mass Spectrometry and Multiplexed Imaging for Spatial Cellular Metabolism), coordinated by Landry Blanc, aims to develop a multimodal imaging pipeline for spatially deciphering cellular metabolism within complex microenvironments. It combines innovative techniques, mass spectrometry imaging (MSI), and multiplexed immunohistology (mHisto), enabling molecular and cellular mapping of the same tissue section. The project will address a major biological question: the uptake of lipids from adipocytes by tumor cells at the invasive front, a process that promotes tumor progression and was first demonstrated in vitro by the team. SpaCELLM will characterize this phenomenon in situ using breast tumor biopsies from patients.
G-quadruplexes (G4s) are non-B secondary DNA structures that fold from G-rich sequences. These structures can be stabilized by small molecules known as G4 ligands. While G4 ligands share a similar ability to interact with G4s in vitro, they display different activities in cells. The TOP2-G4 (Understanding & Tuning the Cellular Properties of G-quadruplex Ligands) project, coordinated by Sébastien Britton, aims to understand, at the structural and molecular levels, how some G4 ligands poison human DNA topoisomerase 2 alpha while others do not. It also seeks to demonstrate that this ability can be controlled, thereby unlocking their therapeutic applications.
The increase in antibiotic resistance among bacterial pathogens is a major concern for human health. In this context, toxin-antitoxin systems encoded by bacteria have emerged as promising candidates for developing alternative antimicrobial strategies. The Patho-TOX (Understanding the Function and Activation Mechanism of Rosmer Toxin-Antitoxin Systems in Bacterial Pathogens) project will focus on the recently identified Rosmer family of toxin-antitoxins (RmrTA), some of which have been shown to defend bacteria against phages. This project, in which Lionel Mourey is a partner, aims to decipher the cellular function and activation mechanism of the RmrTA systems in three major human pathogens: Escherichia coli, Streptococcus pneumoniae, and Staphylococcus aureus. In the long term, this understanding could be used to develop new antimicrobial strategies.
Tertiary lymphoid structures (TLS) are organized lymphoid aggregates that share characteristics with lymph nodes. They have the ability to generate an in situ immune response in chronically inflamed tissues and tumors. The main objective of the ATILA (Targeting Tertiary Lymphoid Structures in Chronic Inflammatory Disorders) project, including Jean-Philippe Girard as a partner, is to develop innovative technologies for the detection of TLS in health and disease.
B cells have a remarkable capacity to modify their immunoglobulin loci. Activated B cells can diversify their antibody repertoire through class switch recombination, which targets the constant genes of the immunoglobulin heavy-chain locus, replacing the initial IgM with IgG, IgE or IgA classes with new effector functions. Non-coding transcription of constant genes and class switch recombination rely on activation signals, and are controlled by long-range regulatory elements, including enhancers and insulators. How does the interplay between the activation signals and the distant regulatory elements modulate the transcription and chromatin dynamics of constant genes along B-cell development is ill-known. The aim of the Dev-CSR project, coordinated by Ahmed Amine Khamlichi, is to tackle the transcriptional and epigenetic mechanisms underlying this interplay, and whose deregulation can lead to B-cell cancers both in humans and mice.
