Since March 2020, Europe has been facing the outbreak of the new coronavirus disease 2019 (COVID-19). This highly contagious infectious disease is a viral zoonosis caused by a virus SARS-CoV-2 from the coronavirus family that emerged in Wuhan in Chine in November 2019, causing first an epidemic that escalated to a pandemic in March 2020. The virus is highly virulent and is spread mainly through droplets from the mouth or nose of the infected person to the person in proximity or in close contact. In the vast majority the SARS-CoV-2 infection is non symptomatic, however, a minority of cases may evolve towards severe forms. The population most at risk of unfavourable outcome are the elderly, people suffering from chronic diseases such as diabetes, obesity or cancer, as well as patients receiving immunosuppressive treatment. In spite of these known risk factors, little is known about why some infected patients may progress to severe disease forms while others remain asymptomatic, and the immune response in the context of COVID-19 remains largely unexplored. Analysis of cellular immune response after non-specific stimulation of T lymphocytes has proven to be useful in predicting the risk of infection in different contexts, including in patients with end-stage kidney disease waiting for a graft in which a lower interferon gamma (IFN-?) level was associated with a higher risk of infection in the year following kidney transplantation. A study on 41 patients infected with SARS-CoV-2 in Huanan seafood market (first identified cases) has demonstrated that while all patients presented with the same symptoms (cough in 76% of cases, fever in 98% of cases), some patients rapidly required mechanical ventilation. These patients in an urgent need of intensive care also presented with a higher level of inflammatory cytokines: IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFa. The aim of our study is to determine the cytokine profile of subjects exposed to or infected with SARS-CoV-2 in order to find biomarkers of developing a mild or a severe form of infection at the moment of their exposure to the virus, and to find biomarkers of developing a mild or a severe form in the course of infection after being diagnosed positive. We believe that the immune system of the infected person plays a major role in determining the evolution of the infection: from the asymptomatic development to mild flu-like symptoms or to acute respiratory distress syndrome (ARDS). By identifying these immune system risk factors we hope to better stratify patients infected with SARS-CoV-2 in order to optimise their medical care and to personalise their treatment: corticoids, immunomodulators or antiviral therapies. Our study concerns two primary research areas: clinical (i) and cellular in vitro (ii) studies. In the clinical part we will quantify the immune response in two populations of patients: - Subjects exposed to a risk of infection with SARS-CoV-2. We will enrol medical personnel in charge of testing, care and treatment of SARS-CoV-2-infected patients at the moment of their first exposure to the virus in their professional environment. We will quantify their Th1 immune response by measuring the level of IFN? in their serum after non-specific stimulation of T lymphocytes. Our hypothesis is that the medical workers with a lower level of IFN? at the moment of exposure are more likely to develop a severe form of the disease once infected. - Patients hospitalized for a SARS-CoV-2 infection. We will correlate the evolution of their inflammatory cytokine profile at D1, D5 and D10 with a risk of developing ARDS. We will then test in vitro (ii) the capability of different therapeutics, such as non-steroidal anti-inflammatory drugs, corticoids, anti-IL6 and chloroquine, to induce the secretion of anti-viral cytokines such as IFN? in the cells of healthy subjects as well as in patients infected with SARS-CoV-2 with different either a mild or a severe form of disease.

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders for which there are limited treatment options, yet which results in significant impairment of quality of life and societal costs. The severity of IBS correlates in multiple paradigms with sugar, and in particular fructose, intake. The current fructose consumption often exceeds the absorption capacity of the small intestine leading to its malabsorption. Previously we showed in rodents that malabsorbed fructose spills over to distal GI tract where it modifies the microbiota composition and an unexpected enteroendocrine cell (EECs) secretory pattern resulting in increased in cholecystokinin (CCK) in the distal region of the gut. Since CCK has been associated with pain signaling, here we propose to investigate the relationships between the microbiota changes resulting from fructose malabsorption, the CCK expression and visceral hypersensitivity. Based on the complementary expertise of the 2 partners involved in the project (intestinal physiology, microbiota, IBS and EEC biology), we will first, investigate, in both rodents and humans, the relationship between the microbiota and the visceral hypersensitivity in the context of fructose malabsorption. Then, we will examine whether CCK mediates visceral hypersensitivity . Finally,we will examine the mechanisms by which malabsorbed fructose induces changes in the EEC features that result in the increase in CCK synthesis. We will use complementary approaches of microbiota analysis (in mice and humans), transfer of intestinal microbiota (mouse to mouse and human to mouse), as well as new mouse genetic models and organoids to decipher the mechanisms involved in the regulation of CCK in distal gut and its role in the development of visceral hypersensitivity. Our results will provide important clinically-relevant information about the mechanisms of hypersensitivity in IBS in the context of fructose malabsorption that may lead to better stratification of IBS patients.

Heat-4P will provide comprehensive knowledge on physiological and social factors increasing vulnerability to the adverse health effects of heat during pregnancy for women and children and new understanding on the biological cascade of events leading to these health effects. We will capitalize on the wealth of individual data on pregnant women and children from 4 longitudinal cohorts and new measure of health biomarkers during pregnancy. We will combine cutting-edge temperature exposure data and advanced methods to capture the chronic and acute effects of heat, and more generally extreme temperatures, and will explore long-term effects of heat on children neurodevelopment. We will disseminate findings through networks of maternal health professionals, population and decision-makers. Heat-4P brings together an unprecedented interdisciplinary team (epidemiologists, physiologists, obstetricians, pharmacologists, biologists, public health professionals) to gain understanding of how heat affects maternal and child health and its social inequalities. Evidence to better identify territories and sub-populations with a higher risk, critical periods of exposure, and risk factors will support effective public health strategies.

Brain damage resulting from traumatic brain injury or subarachnoid hemorrhage is a major cause of death and severe disability. A significant contribution to the morbidity arises from secondary brain ischemic damage. The cornerstone of neurocritical care management is optimization of cerebral blood flow to prevent these secondary damages. The challenge is to detect early signs of ischemia in order to start therapeutic measures. An ideal monitoring technique would enable continuous measurement of cerebral blood flow across the whole brain. Unfortunately, no current method allows such monitoring. We propose to develop a small doppler probe implantable in the skull, using Ultrafast Doppler technology, which is an imaging technic that allows a continuous evaluation of cerebral blood flow. It could provide a continuous monitoring of the cerebral blood flow in several region of the brain, and would constitute an ideal monitoring technique for brain injured patient.