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The aim of this proposal is to explore the mechanisms and fundamental step(s) of tolerance breakdown in the spleen of immune thrombocytopenia (ITP) patients, taking advantage of the unique access to autoreactive splenic germinal centers from these patients as well as of rare cohorts of ITP patients

There is a vast clinical variability among infected individuals, ranging from silent infection to lethal disease. There is also an age-dependent U-shape prevalence curve of life-threatening infections, with children and elderly being most vulnerable. Several inborn errors of cytokines or their respo

CONTEXT: The thymus plays a pivotal role in the establishment of immune central tolerance by producing a diverse repertoire of non-autoreactive T lymphocytes. In particular, the expression of a large diversity of tissue-restricted self-antigens (TRAs) by mature medullary thymic epithelial cells (mTE

Chronic infection by HTLV-1 leads to cancer and/or neurodegenerative disorder and increases the risk of co-infections. Immune dysfunctions have been repeatedly reported in asymptomatic HTLV-1 carriers, indicating that chronic infection induces systemic effects and hampers the ability of the immune s

Papillomaviruses (PV) and polyomaviruses (PyVs) are small nonenveloped, icosahedral DNA viruses that cause persistent infections. Some of these viruses, such as high risk HPVs (eg. HPV16, HPV18...) cause cervical cancer, while others, like BKPyV and JCPyV, cause severe disease in immunosuppressed pa

Shigella is an intracellular pathogen representing an important public health threat. Despite extensive research, there is no universal vaccine against Shigella infections and there is a rise in antibiotic resistance. Shigella targets non-phagocytic epithelial cells of the gut, where it escapes from

Neutrophils play a central role in the human immune response against pathogenic bacteria but also in the regulation of the overall immune response. In the NEUTROGAG project, we propose to characterize a new family of molecules, the glycosaminoglycans or GAGs. The presence of GAGs in neutrophils is s

Phlebotomine sand flies are responsible for the transmission of Leishmania parasites, causing Leishmaniasis, a disease whose wide spectrum of symptoms range from cutaneous lesions to visceral damages. Aside clonal reproduction that causes massive parasite burden in infected individuals, Leishmania e

Tissue-resident lymphocytes represent promising effectors to treat pathologies in tissues. However, because these cells are largely located in tissues, they cannot easily be isolated in humans, and we lack the basic knowledge that would enable their generation in vitro for immunotherapeutic purposes

Survival of living organisms depends on their capacity to develop defence mechanisms against environmental challenges that cause tissue damage and inflammation. These protective functions involve the nervous system and the immune system, two systems traditionally considered as independent. However,

CD95 is a death receptor that belongs to the TNF receptor family. Its cognate ligand CD95L (also known as FasL) is a member of the TNF family. CD95L is a transmembrane protein that interacts with CD95 and can be cleaved by metalloproteases to release a soluble ligand (sCD95L). This cytokine promotes

The HLA gene system (human leukocyte antigens) is extremely polymorphic (more than 20,000 proteins differing by at least one amino acid, distributed over 16 to 20 genes per genome) and is involved in the presentation of peptides to the T lymphocyte, a major player in the immune response. It is the h

Influenza elicits robust immune responses upon infection, including the production of virus-specific antibodies of the immunoglobulin (Ig)M, IgG, and IgA isotypes. In particular, IgA plays a crucial role in protecting lung mucosal surfaces by neutralizing respiratory viruses and impeding their attac

Most of the half a million annual deaths by malaria are due to P. falciparum. This unicellular eukaryote parasite is transmitted by female Anopheles mosquitoes. Malaria symptoms may occur during the intra-erythrocytic part of the parasite life cycle. A P. falciparum infection can result in a wide ra

The rapid emergence of numerous SARS-CoV-2 variants poses a global threat to human health and undermines the goal of achieving herd immunity through vaccination. The overarching aim of VERSATILE is to understand the interplay between cell entry routes and host antiviral responses. This will be addre

Haemophilus influenzae is a bacterium that causes a range of human infections. Since H. influenzae lacks most enzymes of the heme biosynthetic pathway, it has an absolute growth requirement for protoporphyrin IX, the immediate precursor of heme. H. influenzae is one of the few microorganisms able to

IL-1b is a major pro-inflammatory cytokine participating in host protection against infections but also contributing to a variety of highly prevalent conditions including gout, atherosclerosis, diabetes, neurodegenerations. IL-1b is tightly controlled, as it is produced in the cytosol and requires c

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease associated with damage to multiple organs including the salivary and lachrymal glands, as a consequence of abnormal B and T cell responses. Activation of salivary gland epithelial cells (SGEC) drives the pathogenesis of pSS by up-regul

Coronaviruses are positive-stranded RNA, enveloped viruses. The lipidic envelope contains 3 viral proteins with the membrane protein (M) being the most abundant component and the driving force in viral assembly. The main objective of this project is to better understand the morphogenesis of MERS-CoV

Communication is central to the function of all living systems, at all organizational scales (from cells to organs and organisms). It is also crucial to the immune system, where there is a need to tightly coordinate actions from different cells and cell types in order to maintain the integrity of an

Buruli ulcer disease (BUD) is a neglected tropical illness and the third most common mycobacterial disease, after tuberculosis and leprosy. This debilitating and progressive skin disease is caused by Mycobacterium ulcerans (M. ulcerans). BUD is a necrotizing hypodermitis that has received little att

The global rise in antimicrobial resistance (AMR) underscores the critical need to target the mechanisms that limit the effectiveness of antibiotics, promote the development of resistance and lead to treatment failures. In addition to classical drug resistance, the effectiveness of antibiotics is al

Enteric pathogens must integrate multiple environmental signals including differences in O2 tension and oxidative stress to successfully establish themselves within complex and diverse gut micro niches. Clostridium difficile (CD) appears to be a good model to decipher the impact of these environment

The proposal is based on strong preliminary data showing that translation of pre-spliced mRNAs generates peptides for immune tolerance for the major histocompatibility (MHC) class I pathway. We have introduced an antigenic peptide sequence (SL8 from chicken ovalbumin (Ova)) in the second intron of t

Clostridioides (Clostridium) difficile is the major cause of nosocomial infections associated with antibiotic therapy. The disruption of the colonic microbiota by broad-spectrum antibiotics promotes colonization of the intestinal tract by this pathogen. Due to the increase of severe forms associated

Induction of the unfolded protein response (UPR) has emerged as a key regulatory mechanism that controls inflammatory processes, notably in response to infections. We recently demonstrated that induction of the UPR sensor IRE1 in dendritic cells (DC) infected by the intracellular parasite Toxoplasma

The Ikaros family of transcription factors (TFs) comprises related zinc finger proteins that are differentially expressed in hematopoietic cells and essential for immunity. In humans, polymorphisms in the genes encoding Ikaros family members are linked to autoimmune and inflammatory diseases, while

Inflammatory bowel diseases (IBDs) are debilitating diseases that affect profoundly the lifestyle of over 5 million persons worldwide. IBDs are characterized by alternating periods of remission, and relapse whose mechanisms are obscure. Imbalanced immune responses against commensal bacteria are the

Heterogeneity in microbial virulence is commonly observed between strains of the same species. In clinical settings, this diversity might be associated with the emergence of clones associated with specific pathologies or specific hosts. A major driving force in the diversification of bacterial patho

According to the latest WHO’s World Malaria Report, there were a total of 241 million cases of malaria in 2020 leading to 627 000 deaths, mostly children under five years of age, principally associated with Plasmodium falciparum infection occurring in sub-Saharan Africa. Human malaria severe disease

Immune responses to infection are highly variable among different populations. We hypothesize that variability in immune pathways, between and within female and male populations, differentially impacts how immune responses arise following exposure to bacteria. Our objective is to understand how sex

Initiation of antiviral immune responses requires a coordinate action of innate signaling, including NF-kB and interferon (IFN) pathways, and induction of adaptive immunity, through the processing and presentation of viral antigens by MHC molecules. TAX1BP1, a member of the SQSTM-1-like selective au

In the course of the ANR-funded ROXANNE (2017-2021) project, we have characterized a novel innate immunity pathway functioning in the control of viral infections in the model organism drosophila. This pathway involves the evolutionarily conserved molecule STING, which activates an NF-kB-dependent tr

Type 1 diabetes (T1D) results from the destruction of pancreatic islet beta cells by autoimmune CD8+ T cells. We hypothesize that beta cells play a key role in their own autoimmune demise, by increasing their immune visibility and vulnerability. Our analysis of the beta-cell peptidome identified nov

Hematopoiesis is the process by which hematopoietic stem (HSC) and progenitor cells (HSPCs) create tens of billions of new immune cells each day. Large amounts of protein, lipids, nucleotides and ATP are required to sustain this high rate of biosynthesis, but the role of metabolism in hematopoiesis

Malaria remains a major public health problem. Of the five species of Plasmodium implicated, P. vivax is the most widespread outside Africa and, although less lethal than P. falciparum, it is responsible for debilitating and even severe illnesses. The recent discovery that certain tissues, namely bo

Effective T cell responses against pathogens rely on a highly dynamic regulation of genetic programs for ample production of cytokines, chemokines, and cytotoxic molecules. The transcriptional networks that control T cell differentiation and activation are well studied. However, genome-wide studies

Mitochondria act as critical metabolic hubs and signalling platforms, and understanding the potential of mitochondrial DNA and RNA to act as immune-modulators in the context of homeostasis and disease is an area of intense scientific focus. Notably, there is increasing recognition that aberrant enga

Foreign double stranded (ds)RNA sensing by cellular factors is a conserved mechanism in antiviral innate immunity. Recognition of self dsRNA structures can also trigger the innate immune system under certain conditions such as autoimmune diseases in humans. Whether endogenous dsRNA sensing plays a r

Immunoglobulin class switch recombination (CSR) is initiated by cytidine deamination in DNA mediated by activation induced cytidine deaminase (AID), by the subsequent excision of the resulting uracils by Uracil DNA glycosylase (UNG) and by DNA cleavage through AP endonucleases. Although uracils aris

Bacterial lipopolysaccharide (LPS) is a key virulence factor for both innate and acquired host responses to infection. Intriguingly, Legionella pneumophila (Lp) serogroup 1 (Sg1) strains, are responsible for over 80% of confirmed Legionnaires’ disease cases, a severe pneumonia that is often fatal wh

Sjögren's syndrome (SjS) is a chronic autoimmune disease characterized by the destruction of exocrine glands by self-reactive immune cells. About 0.5% of the population is affected with dry mouth and eyes and there is no cure against the disease. The immunopathology of SjS is complex and associated

The current COVID-19 pandemic put the world in an unprecedented situation, with a wide influence on our daily lives. Increasing evidence indicates that short- and long-term neurological complications are associated to SARS-CoV-2 infection. However, minimal information regarding the impact of the vir

Lymphoid stroma comprising endothelial and mesenchymal cells plays an increasingly recognized role in the regulation of the immune response and therefore presents novel targets for immunotherapies. Lymphatic endothelial cells activated by the TNFR-superfamily member RANK create an immune cell niche

Type 2 innate lymphoid cells (ILC2s) share cytokine and transcription factor expression with Th2 lymphocytes. ILC2s promote tissue repair and immune responses to parasitic infections in mucosal barriers. They regulate Th2 environmental and tissue metabolic homeostasis in numerous tissues like the

Natural killer (NK) cells are implicated in the control of tumors and viral infections, including HIV-1 infection. NK cell activity is tightly controlled through the balance of a large repertoire of inhibitory and activating receptors. In the last years, the new-generation technologies allowed to u

Viruses depend on host cell metabolism for their replication. As such, they have evolved sophisticated mechanisms to interfere with specific metabolic pathways in order to fulfill their need in energy and biosynthetic intermediates. On the other hand, it has been shown that signaling of innate immun