It is currently difficult to know the proportion of children immunized during thE sars-cOv-2 epidemic. Moreover, there is still uncertainty about whether adaptive immune responses to SARS-CoV-2 are protective. Such knowledge is of immediate relevance, as it will provide insights into immunity of SARS-CoV-2 infection and thus help define future immunization strategies. On the other hand, SARS-Cov-2 is associated with an overall higher rate of medical complications in immunocom¬promised patients than in the general population. However, the clinical significance of SARS-CoV-2 varies among different immunocompromised populations, and this is related to the individ¬ual degree and type of immunosuppression. Thus, the quantitative and qualitative evaluation of specific B and T cell responses in COVID-19-infected children with either acquired or iatrogenic disruption of their immune system is needed. So, we plan to analyze the anti-SARS-CoV-2 humoral and memory T cell responses, in children with different levels/type of immunosuppression and healthy controls seen in 4 University Hospitals in Paris, in order to determine and compare the quantity and quality of their SARS-CoV-2 specific humoral and memory T cell responses. Children will be prospectively enrolled a case-controlled cohort at the time of usual referring for their pathology and additional blood samples will be collected during blood sample needed for the conventional care of the patient. Several groups of immunosuppressed children (children with HIV infection, Hematologic Malignancy treated by conventional chemotherapy or allogenic stem cell transplantation, inflammatory bowel disease treated by anti-TNF, idiopathic juvenile arthritis treated by methotrexate, children treated by renal transplantation) and subjects considered as control (consultation in pediatric surgery department) will be included. Humoral specific responses will be evaluated by the quantification of SARS-CoV-2 antidodies (IgG and IgM) (Chimiluminescence) and of the SARS-CoV-2 neutralizing antibodies (pseudovirus neutralization assay). Ex vivo SARS-CoV-2-memory T cell responses will be evaluated on frozen cell, in a subgroup of patients with specific antibody, using intracellular cytokine staining (IFN, IL2, TNF) followed by multiparameter Flow Cytometry. In the absence of detection of specific T cells after ex vivo analysis, in vitro analysis of memory T cells responses will be performed by IFN- ELISpot assay after 11 days of stimulation with specific peptides. Patients inclusion, main objective analysis (rate of patients with humoral immunization against SARS-CoV-2 in different group of immunosuppressed children in comparison to control children), and secondary objective analysis (anti-SARS-CoV-2 Humoral and cellular T cell responses, link between anti-SARS-CoV-2 humoral and cellular immune responses) will be performed in 12 months. Such specific study of the pediatric population is particularly important in order to determine their potential for individual and collective protection, especially in immunosuppressed children. These immune parameters will allow to deeply assessing for each child the risk of infection in relation to the persistence of the circulation of the virus. Moreover, with regards to collective benefits, this study should make it possible to adapt the level of protection needed by these children at higher risk of infection by SARS-CoV-2. Finally, the vaccination of immunocompromised patients is an important priority. The 2009 H1N1 influenza pandemic had further highlight the need of immunocompromised individuals to generate a protective and sustained immune response. So, additional researchs to characterize specific immune responses are important in populations receiving varying immunosuppressive regimens. This study should help to adapt future vaccine strategies against SARS-CoV-2 when they will be available.

Improving early recanalization and preventing neurovascular damage at the acute phase of ischemic stroke are the main objectives of current stroke research. In contrast, much less attention is being paid to the possibility of reversing and repairing post-stroke neurological damage. Previous studies, including ours, have indicated that pro-angiogenic and immunomodulation-based therapies can stimulate post-stroke cerebral remodeling and healing, thus decreasing infarct volume, improving sensorimotor deficit but also preventing cognitive decline. Remarkably, although the healing properties of platelets have long been known and taken advantage of in regenerative medicine, data on the role of platelets in post-stroke cerebral plasticity are scarce. Our previous studies and preliminary results show that in addition to storing large amounts of growth factors, platelets are the main source of various factors involved in post-stroke recovery, including brain-derived neurotrophic factor, angiopoietin-1, TGF-beta, serotonin and dopamine. In fact, our results obtained from a cohort of thrombocytopenic patients show that low platelet counts are associated with a significant decrease in those factors' plasma levels. In addition, our results obtained in experimental stroke models in mice indicate that platelets play a vital role in the days following an ischemic stroke, and that platelet inhibition by aspirin as used in secondary prevention post- Stroke worsens cognitive decline. In this context, our translational research project aims at determining the mechanistic contribution of platelets to cognition and post-stroke cerebral plasticity. This is of utmost importance since antiplatelet therapy is the main treatment given to stroke patients for secondary prevention.

CADASIL is an adult-onset, dominantly inherited neurovascular disorder caused by NOTCH3 mutations. It is characterized by a variable spectrum of symptoms, even within families, including recurrent subcortical infarctions, dementia, and less frequently, migraine and psychiatric symptoms. We have recently discovered that the p.Arg1231Cys mutation is present at a very high frequency in a founder population in Italy (Nutile et al. 2019). Through comprehensive neurological evaluations (incl. MRI) and vascular risk factor collection in this population, and by comparison with well characterized patient samples from Lariboisière Hospital in Paris, this proposal aims to investigate the CADASIL pathogenesis and phenotype variability for p.Arg1231Cys mutation, to identify novel biomarkers through possible correlations between clinical phenotypes, and to detect novel genetic factors through genome-wide association studies and Identity-by-descent analyses.

To date, dynamics of transmission of Multi-Drug Resistant Enterobacteriaceae (MDR-E, including Extended-Spectrum Beta-Lactamase and Carbapenemase-Producing Enterobacteriaceae) have been mainly studied in hospitals. Several studies suggest, however, that MDR-E spread widely in the community through human-to-human transmission. This multidisciplinary project will, using microbiology, epidemiology and mathematical modeling techniques: 1) estimate transmission rates of MDR-E from an index case to his/her household members, and 2) identify the epidemiological and microbiological factors associated with transmission (genomic characteristics of strains, relative faecal abundance, influence of the microbiota). Knowledge gained will inform decision makers and scientists with respect to the impact of control strategies to specifically control the spread of multidrug-resistant microorganisms in the community.