Plasma cells and the antibodies they secrete are essential for long-term protective immune responses and tissue homeostasis. However, they can also contribute to the pathology of numerous inflammatory and autoimmune conditions. Despite their relevance in health and disease, the mechanisms underlying antibody production and secretion are still poorly understood. This is an essential question as a better characterization of the involved molecular actors may pave the way to improved antibody production, and to the development of new therapies for antibody-driven diseases. Preliminary data obtained in our laboratory showed that the Sec22b SNARE is essential for antibody secretion but also for plasma cell maturation. Using a conditional mouse model we observed in absence of Sec22b in the B cell lineage an almost complete lack of circulating antibodies and a dramatic decrease in the number of plasma cells in the spleen and the bone marrow. We now plan to use this model to address how Sec22b affects plasma cell fitness and antibody secretion. In parallel we will determine the impact of such defects on the normal and pathological humoral immune response and on tissue homeostasis, in particular in the BM. Collectively, this project should bring new lights on the molecular mechanisms underlying antibody secretion by plasma cells, a key process with huge relevance both at the therapeutic and at the industrial levels but largely overlooked so far. Moreover, our model will allow us to study with great details the impact of plasma cells and antibodies on homeostasis and inflammation at the tissue and organism level.

Approximately 50% of patients require prior bone regeneration procedures to enable dental implant placement. The treatment of such bone defects still remains a surgical challenge for oral surgeons. Guided bone regeneration (GBR) is the most commonly used technique. This procedure is based on the principle of space maintenance within a bony defect by using a barrier membrane: the membrane is applied over a bone defect, creating a secluded space between the bone and the membrane thereby maintaining the bone substitute and allowing proper bone remodeling. Two main types of membranes are currently used for GBR: 1) non-resorbable and 2) resorbable membranes. They both show substantial limitations. The stiffness of non-resorbable membranes often cause soft tissue dehiscence leading to membrane exposure in 30% of cases and subsequent bacterial contamination. Furthermore, they are difficult to remove and require an additional surgical procedure to be removed. Resorbable membranes show weak mechanical properties, limiting their applications to smaller bone defects regeneration. The project is based on the following research hypothesis: improved GBR outcomes can be achieved through the use of a hybrid membrane. We thus propose to develop a multi-layer composite membrane combining a biological and a synthetic layer. This project is divided into four parts: WP1) Development of a multi-layer composite membrane, WP2) Assessment of its cytocompatibility in vitro and its ability to promote cells osteodifferentiation, WP3) Assessment as a GBR membrane in vivo in a bone defect model in small animal, and WP4) Comparison of the multi-layer composite membrane to conventional membranes used for GBR in a large animal model in vivo, close to human bone defects. The PI of this project and her team have the technical and clinical skills needed to develop this innovative membrane that addresses a public health problem. The PI of this project and her team have the technical and clinical skills needed to develop this innovative membrane that addresses a public health problem.

Autoimmune diseases represent an increasing burden on global health, with a steadily rising incidence and a consistent association with chronic illness and premature death. Despite this, therapy often relies on non-specific and potentially toxic immunosuppression, which carries its own morbidity. The recent development of antibody-mediated therapies has shown great promise for the treatment of several autoimmune diseases demonstrating that the development of specifically targeted therapies is the way forward for the treatment of these disabling conditions. Autoimmune disease are complex conditions characterized by a deregulation of the immune system that can implicate several cell types including B and T cells and affect different organs. Thus, we need to gain a better insight into the biology of the cells involved in these pathologies if we are to design and develop safer and more efficient therapies. The proposal AUTO-PLASMO focuses on plasma cells - the cells that are responsible for antibody production within the adaptive immune system. Plasma cells play an essential protective role against infection but they are also implicated in the pathology of several autoimmune diseases including systemic lupus erythematosus via secretion of pathologic autoantibodies. Despite their essential role in health and disease, how plasma cells are generated, survive and secrete antibodies is still not fully elucidated. Moreover, plasma cells are resistant to most therapies currently used to treat autoimmune disease. There is thus a knowledge gap that needs to be filled in order to offer new therapeutic options for the control or elimination of this cell subset. This question forms the core of this research project that is divided in three complementary axes: -Identification of new regulators of plasma cell survival and antibody secretion in health and disease. -Analysis of plasma cell phenotypic and functional heterogeneity in health and disease. -Characterization of plasma cell survival and migration in inflamed tissue in systemic lupus erythematosus. These three axes form an integrative approach combining basic immunology techniques with innovative single-cell methods to study plasma cell function and survival in health and disease, which in turn could facilitate the identification and validation of new therapies that target this cell subset.

Infections are a major health issue worldwide and antibiotic resistance is a serious public health threat. Pseudomonas aeruginosa is a critical priority 1 for research and development of novel therapies, considering high prevalence, high mortality rates, and limited therapeutic options. It is particularly important in people with chronic lung diseases such as people with Cystic Fibrosis (pwCF), a rare genetic disease characterized by chronic bacterial lung infections, notably by the bacteria Pseudomonas aeruginosa. Acquisition of microbial infection is a key step in the course of CF lung disease severity and there is no way to predict which patients are at the highest risk of being infected by these bacteria. Since airway epithelial cells (AEC) are constantly exposed to pathogens through respiration and have a pivotal role in the orchestration of the lung immune response, a better understanding of the interaction between AEC from pwCF and bacteria will allow to develop alternative/complementary strategy to antibiotics and to improve patient follow-up. In this research project will study the contribution of septins, proteins known to have an emerging role in microbial infection. Their role in the lung, one of the major exposed tissue to bacteria has never been investigated and may constitute new therapeutics targets in the development of new therapeutic strategies besides antibiotics. Complementary, in a translational approach their involvement as susceptibility genes of infection by P. aeruginosa in pwCF would serve as biomarkers to identify and follow in a personalized way, people at higher risk to be infected by this pathogen.

Alzheimer's disease (AD) is a multifactorial disease for which several molecular and functional abnormalities are now well known. Among these, neuronal excitotoxicity on neurons leads to synaptic loss and build-up of DNA double-strand breaks (DSB) that drive neurodegeneration and cognitive decline. A role for adaptative immunity, and inflammation due to chronically activated microglia has been suggested as a trigger and regulator of AD, but the neuroimmune interplay that underlies neuronal excitotoxicity and dysfunction remains ill-defined and is certainly diverse. As a common neurotropic brain-persisting pathogen, which infection is tightly controlled by specific immune responses, the parasite Toxoplasma gondii (Tg) may impact on the progression of AD. Supporting this hypothesis, our interdisciplinary consortium has gathered preliminary data showing aggravation of Tau pathology, inflammation dominated by Il-1b signaling and earlier onset of cognitive decline in models of Tauopathy or amyloidosis infected by latent Tg. We have also shown the instrumental role of DSB on spatial memory deficits promoted by Tg. In our project NinTenDo, our overarching goal is to decipher the molecular mechanisms and determinants that promote the progression of AD pathology in the brain of two Tg-infected transgenic mouse strains, modeling the two major lesional determinants of AD, i.e., tauopathy and amyloidogenesis. Our specific aims will be i) to identify specific neuro-immune signatures induced by chronic Tg infection in AD brains, with specific correlation with AD outcome progression; ii) to evaluate the specific contribution of neuronal vs. microglial IL-1b signaling to Tg-induced progression of AD pathology. Overall, this project will allow to decipher mechanisms that may link AD to pathogen persistence in the brain, and will improve our understanding on new regulatory mechanisms of neuro-immune pathophysiology of cognitive decline.