Schistosoma mansoni as epimutator of murine hosts and its epigenetic plasticity

Abstract

Schistosomiasis is a parasitic disease caused by helminths of the genus Schistosoma that affects about 240 million people worldwide. Brazil is the South American country with the highest incidence of the disease, due, among other factors, to the presence of the intermediate host in endemic regions. It is worth mentioning that, despite praziquantel having an efficiency of 90.3% of success in treatment according to the National Survey on the Prevalence of Schistosomiasis mansoni and Geohelminthiasis (2018), it is still necessary to overcome some important obstacles in the treatment, such as the emergence of resistant strains in some endemic regions, absence of infant formula and treatment abandonment due to pharmacological side effects, which reinforces the importance of finding alternative or complement approaches to deal with the disease using todays high-throughput biotechnological tools. Therefore, we wish to address an important question about S. mansoni that is still poorly understood and which perhaps would explain, at least in part, the difficulty in obtaining new drugs and vaccines: its role as (i) an epimutator of its host, and (ii) the adaptive plasticity of its epigenome. Thus, the objective of this work is to analyze the effects of S. mansoni infection on the transcriptome and epigenome in the mammalian vertebrate host (mouse), as well as to identify the molecular pathways affected by the pathogenesis. For this, methodologies involving experimental and in silico analysis will be used. The current project will be organized into 2 complementary research objectives: In the objective 1 we propose to analyze the effects of experimental S. mansoni infection on the transcriptome and epigenome of mice as vertebrate hosts to identify the epigenetic and molecular pathways affected by pathogenesis. The underlying hypothesis is that the parasite uses epigenetic mechanisms to reprogram the host's immune memory. In objective 2, we will extend the previous study of histone posttranslational modification, silencing the genes responsible for specific histones PTMs from parasite. In the objective 2, we aim to extend the study of the specific PTMs in the parasite. The expectation is that these results will be used to design inhibitors that target epigenetic pathways, with the potential to suggest new drugs or drug repositioning. Thus, with this project we intend to generate knowledge about the epigenetic response of hosts to S. mansoni infection and vice-versa and propose new strategies for the treatment and control of schistosomiasis, an important disease both in Brazil and worldwide (AU)