BrFrSCHISTO

Three hundred million people are infected with schistosomes that cause severe debilitating hepatic disease, for which there is no effective treatment, in 5 to 30% of these people. The disease is caused by the inflammation triggered by eggs in the liver, leading to massive hepatic fibrosis (HF) and organ dysfunction in some subjects. Tissue fibrosis results from changes in the production and destruction of extracellular matrix (ECM). The mechanisms underlying ECM protein deposition and turnover are beginning to be unravelled, but much remains to be done if we are to understand fibrosis in this specific disease context. Furthermore, the crucial question of why some subjects display rapid progression to severe stages of fibrosis (SHF) whereas others do not progress beyond mild fibrosis (MHF) remains unanswered, not only for schistosomal fibrosis, but for HF in general. Animal models have provided important insight into the possible mechanisms of schistosomal fibrosis. However, it is difficult to reproduce all the characteristics of human schistosomal fibrosis in laboratory animals. We have previously reported a genetic control of HF by the 6q23 locus and demonstrated that SNPs in two genes at this locus account for this effect in Brazilian, Sudanese and Chines populations infected with S.mansoni and S.japonicum. Our project is to combine a search of the genetic variants associated with SFH (GWAS) on the whole genome of patients with severe and mild FH with an analysis of the transcriptome of the livers of the same clinical groups that will identify metabolic pathways associated with hepatic disease. This strategy should allow the identification of metabolic pathways crucial in SHF and universal markers of SHF. We shall analyze the transcriptome of liver biopies from 50 SHF, 20 MHF and 30 healthy controls. Our pilote study shows that the transcriptome analysis will unable us to identify several metabolic pathways associated with SHF. The GWAS will be performed on 800 SHF and 800 MHF in Brazil (S.mansoni), SNP selection for further analysis will be carried out using the results of statistical and transcriptome analysis. The selected SNPs will be confirmed in a second Brazilian (500 SHF, 500 MHF) and Sudanese samples infected with S.mansoni. This strategy should detect most varaints including those with weak effects. The variants confirmed in both populations will be tested in Chinese (500 SHF, 500 MHF) infected with S.japonicum (more pathogenic than S.japonicum). Combining results of the GWAS with the observations of the transcriptome analysis will bring the convincing demonstration of metabolic pathways involved in SHF and of universal genetic markers of SHF which will lead to the identification of the causative variants in the same genes. These genes will be targets for chemotherapy. As some of the pathways and regulatory mechanisms underlying fibrosis in general are probably involved in the induction of fibrosis by schistosomes, some of our findings will undoubtedly have implications for hepatic fibrosis of other aetiological origins such as HCV induced fibrosis. This project is rendered feasible by the extensive experience of the partners in collaborative studies of schistosomiasis. This programme will bring together laboratories with a high degree of expertise in the clinical management, epidemiology and immunology of schistosome infections and in the genetics of complex diseases