Rotaviruses (RVAs) are the most common cause of acute gastroenteritis in children. The disease frequently requires hospitalization and annually causes the death of several hundred thousands children in low-income countries. Two live vaccines have been developed and both show remarkable efficacy in high-income countries, but unfortunately and for unknown reasons they prove much less efficient in several regions of lower income. Nonetheless, recent data on the glycan-binding properties of human RVAs unexpectedly offered a potential clue to understanding of this limitation. RVAs are known to interact with glycans of the host cell membrane through their VP4 spikes, more specifically by the VP8* outermost domain. Until recently it was considered that, depending on the strains P-genotype characterized by genetic variation of the VP4 protein, interacting glycans contained sialic acid motifs, either sensitive or resistant to sialidase treatment. The new data indicate that human RVA strains additionally bind to neutral fucosylated glycans of the histo-blood group type (HBGAs). These carbohydrate antigens are located at the termini of either O-linked or N-linked glycan chains of proteins and of lipids and are expressed mainly on epithelial cells. They are characterized by an extensive genetic variation caused by common polymorphisms at the ABO, FUT2 and FUT3 loci. These genes encode glycosyltransferases that contribute in concert to the synthesis of the ABH and Lewis antigens that define the ABO, secretor and Lewis phenotypes. The VP8* of some strains appears to recognize the Leb difucosylated motif, whilst others bind to the A blood group antigen. Based on a limited number of cases, we and others observed that individuals lacking a functional FUT2 enzyme (nonsecretors) were never found among children with severe rotavirus gastroenteritis, suggesting resistance to infection by the common P[8] strains. This is consistent with the requirement of a functional FUT2 enzyme in the synthesis of the Leb ligand. Others additionally observed that children infected with P[6] strains were found among Lewis positive (FUT3+) only, suggesting that different strains may have different HBGAs specificities and may recognize distinct subgroups of the population. The vaccine strains contain a VP8* of the P[8] type and may not infect FUT2- or FUT3-null children. Since the frequencies of HBGAs polymorphisms greatly vary across geographical locations such refractory individuals may represent up to 50% of the population in some areas. We hypothesize that the lack of vaccine efficacy in many children of those areas could be due to an absence of HBGA ligand and that due to the higher diversity of circulating virus strains in tropical areas, the vaccine refractory children may remain susceptible to strains other than those of the common P[8] type. The aim of our project is to document this hypothesis through the combination of a prospective genetic study, analyses of the glycan specificity of the VP8* from clinical and vaccine strains and of in vitro experiments aimed at characterizing the role of HBGAs binding in the infection process. The prospective study will be carried both on a western European population in Nantes and a population from a tropical area at Cayenne (French Guyana). RVA infected children admitted at the pediatric emergency units at both locations will be enrolled alongside non-infected control groups. Virus genotypes as well as patients and controls HBGAs subtypes will be determined in order to uncover a relationship between them. Glycan specificity of the VP8* of strains of diverse P-genotypes will be determined using glycan microarrays and saliva mucins of diverse HBGA phenotypes in order to control for a match with the infection data. HBGA involvement in the infection process will be assessed using cultivable strains through manipulation of the glycan expression of susceptible cells lines under conditions mimicking in vivo infection.

Some malaria parasites, and in particular the highly prevalent Plasmodium vivax in humans, produce hypnozoites that are dormant liver forms that activate months to years after the initial infection to produce relapse episodes. This poses a serious hurdle to the control and elimination of malaria in many of the endemic regions of the world. Toxicity concerns restrict the deployment of the only available drug (primaquine) that can eliminate hypnozoites. Thus, novel safe anti-hypnozoite drugs are urgently needed. However, in the absence of a in vitro model, screening for such drugs or indeed investigations on hypnozoites that might guide drug discovery hypnozoite have remained severely limited by the inability to access sufficient material from infected host livers. We have recently developed the first protocol for the in vitro cultivation of hypnozoites in their natural target cells, the primary hepatocyte, thereby making it possible for the first time to investigate hypnozoite biology. In a preliminary screen, we identified an inhibitor of histone methyl transferase, an enzyme implicated in the epigenetic control of gene expression in malaria parasites, which induces the activation of hypnozoites to resume maturation. This opens new avenues to develop a radical cure and to expand knowledge on the nature and role of epigenetic control during the malaria life cycle. Specifically we wish to screen a library of histone methyl transferase inhibitors with a view of identifying one or more lead compounds worthy of further development. We also aim to identify which of the parasites’ many histone methyl transferases are implicated, and initiate investigations on the molecular basis of the control of hypnozoite quiescence. The ultimate goal is to apply this data to rationalize the search for novel drugs that will lead to eliminate hypnozoites and their associated relapse episodes.

Major Depressive Disorder (MDD) is a highly prevalent disorder. The diagnosis of MDD is usually based on clinical interview with collection of symptoms affecting cognition, emotion and behavior. In order to improve early diagnosis and to define homogeneous group of patients better suited for treatment, we clearly need diagnosis of mental disorders based upon pathophysiologic processes. Genetic and environmental factors influence the onset, maintenance and longitudinal course of MDD. Among these environmental factors, interpersonal stress and life-events involving social rejection may precipitate depressive episodes. MDD is also associated with disengagement from professional and vocational commitments. This suggests MDD has tight links with social functioning. Moreover it has recently been emphasized that social cognition is a good predictor of functional and social outcome of depressed patients. Neurobiological mechanisms of social difficulties of depressed patients are unknown. The main objectives of SENSO are to define social related biomarkers of MDD. SENSO will specifically focus on social inclusion and exclusion and other forms of social-psychological threats to define related biomarkers for early diagnosis and follow-up of patients with MDD. This project uses a multidisciplinary approach combining brain imaging, immunological, virtual reality and cognitive experiments to study the biological bases of social impairment in MDD. SENSO will bring expertise from cognitive-social psychology, cognitive neuroscience, immunology and clinical psychiatry to define new pathophysiologic pathways. Our main hypothesis is that depressed patients showed heightened sensitivity to social signal reflecting impairment in basic social processes that monitor social acceptance. The project will include 60 depressed patients and 150 healthy controls. Patients and controls will be simultaneously examined with multiple experimental tasks. The project is composed of 5 workpackages that evaluate behavior, cognitive, biological and neural biomarkers of sensitivity to social signal in MDD. Throughout the project patients and controls will participate to experimental tasks assessing sensitivity to dynamic social signal, social attention, sensitivity to criticism or approbation from others, social exclusion and abilities to socially reconnect after exclusion. Cognitive performance, EEG and functional MRI, behavior and relationships between pro-inflammatory cytokines and social stress will be systematically assessed in depressed patients and controls. Our multitasking approach will provide the opportunity for a better definition of phenotypes of MDD associated with social impairment. Additional possible output of the project also includes the development of specific devices and tools for cognitive and social remediation. Overall this project contributes to the development of personalized medicine tailored to the specific needs of patients suffering from major depression.