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 with an intricate crosstalk between various cell types including salivary gland epithelial cells (SGECs), lymphocytes, and innate immune cells. Recent research in the field of autoimmunity, revealed the critical role of antimicrobial peptides (AMPs) in preventing these diseases via their strong immunoregulatory capacity. Among them the secretory leukocyte protease inhibitor (SLPI) is highly expressed by the acinar cells in the SGs. SLPI present in the extracellular milieu can penetrate neighboring cells and modulate the function of various immune cells. Our objective is therefore to determine the role of SLPI in the exocrine glands during the development of SjS in murine models and using patient samples. Our project will provide new perspectives in the immunopathology of SjS and could offer new therapeutic opportunities.

The recent and ongoing outbreak of Ebolavirus in West Africa has made it obvious that we are currently ill-equipped to deal with this virus in terms of our ability to effectively treat victims on a large scale in countries where access to health care systems is scarce. At the heart of this inability is the fact that we still do not know exactly how and why this virus is so deadly upon infection. The need for a better understanding of the molecular mechanisms involved in high pathogenicity is increasingly vital for or ability to continue to develop and refine treatment strategies. The overall goal of this project is to gain significant insights into the mechanisms of EBOV-induced pathogenicity and in particular into the role that the viral protein shed GP plays in the dis-coordination of host immune and hemostatic processes. Specially, we aim to determine the mechanism by which this viral protein is able to bind host cells and serum factors and to activate processes that are critically linked to the survival of an Ebola virus infected patient. The role of shed GP in the activation of a range of host cells and immune processes will be studied in detail, as well as its potential role in the disruption of coagulation. Using innovative system immunology tools and reverse genetics approach we will study the immune response in guinea pigs infected with Ebolavirus over time, in order to reconstruct the exact processes of cellular and inflammatory responses to infection and to identify key inflammatory pathways involved in protection. Finally using small-animal models we will show the potential of a novel range of therapies for Ebola virus disease.

Renal diseases are a worldwide health problem: more than 500 millions of people in the world (2-3 millions in France) have some degree of kidney damage. Many may evolve into more advanced stages. The cost of renal diseases is a burden to the economy, as population is ageing, and diabetes and high blood pressure, the most frequent causes of renal damage, are increasing. Acute kidney injury (AKI) occurs in approximately 15% of hospitalized patients and up to 40-60% of intensive care unit patients; it appears now as risk factor for developing chronic kidney disease and, particularly, for promoting the transition of chronic kidney disease (CKD) to end-stage renal disease (ESRD). In developing countries many patients cannot be treated either with dialysis or renal transplantation due to cost, availability of kidney transplant or health structures. Therefore, preventing or treating early stages of renal diseases on one hand and decreasing graft dysfunction on the other hand are major challenges in the field. The benefit of the Mineralocorticoid Receptor (MR) blockade is now demonstrated, based on evidence of its capacity to limit the morbidity and mortality in cardiovascular diseases (cardiac failure, post-infarctus), and possibly in other end-stage organ failure. The aim of this project is to study the underlying mechanisms and the therapeutical potential of MR antagonism in preventing the decrease of renal function associated with ischemia-reperfusion. Preliminary data from the all the Partners indicate that pharmacological blockade of MR is beneficial to prevent renal damage, especially when alteration in renal hemodynamics is involved. Working hypothesis: Since the Aldosterone/MR pathway activation participates to the control of vascular function and inflammation, we propose as working hypothesis that part of the effects of MR antagonists (MRA) in IR injury (IRI) is related to the inhibition of vascular MR. Moreover since inflammation is secondarily induced by acute renal ischemia, we will assess whether MR in macrophages is involved in the chronic consequences of acute kidney injury. To this purpose, we wish to combine 1) pharmacological studies using MRA, 2) experimental approaches on mice with altered levels of MR in the vascular endothelium, in the smooth muscle or in macrophages submitted to renal injury, 3) studies in a large animal porcine model of warm and cold ischemia. This step is a prerequisite to evidence-based evaluation of the potential benefits of MRA in related contexts in patients. Improvement of renal outcome should then be easily translated into human pathology trials. The added value of this project is the effort to link fundamental research approaches to pre-clinical proof of concept to yield novel therapeutic outcomes in nephrology. It will provide new mechanistic insights into the effects of MR activation in renal diseases as well as on the beneficial effects of MRA in these clinical settings.