Abstract
Schistosoma mansoni adaptive success is related to regulation of replication, transcription and translation inside and outside the intermediate and definitive host. We hypothesize that S. mansoni alters its epigenetic state in response to the mammalian host immune system, reprogramming gene expression and altering the number of eggs. In response, a change in the DNA methylation profile of hepatocytes could occurs, modulating the extent of hepatic granuloma. To investigate this hypothesis, we used the EBi3-/- murine (Mus musculus) model of S. mansoni infection and evaluated changes in new and maintenance DNA methylation profiles in the liver after 55 days of infection. We evaluated expression of epigenetic genes and genes linked to histone deubiquitination in male and female S. mansoni worms. Comparing TET expression with DNMT expression indicated that DNA demethylation exceeds methylation in knockout infected and uninfected mice and in wild-type infected and uninfected mice. S. mansoni infection provokes activation of demethylation in EBi3-/-I mice (knockout infected). EBi3-/-C (knockout uninfected) mice present intrinsically higher DNA methylation than WTC (control uninfected) mice. EBi3-/-I mice show decreased hepatic damage considering volume and reduced number of granulomas compared to WTI mice; the absence of IL27 and IL35 pathways decreases the Th1 response resulting in minor liver damage. S. mansoni males and females recovered from EBi3-/-I mice have reduced expression of a deubiquitinating enzyme gene, orthologs of which target histones and affect chromatin state. SmMBD and SmHDAC1 expression levels are downregulated in male and female parasites recovered from EBi3-/-, leading to epigenetic gene downregulation in S. mansoni. Changes to the immunological background thus induce epigenetic changes in hepatic tissues and alterations in S. mansoni gene expression, which attenuate liver symptoms in the acute phase of schistosomiasis.
Highlights
Schistosoma mansoni is a helminth parasite that causes schistosomiasis, a disease affecting about 200 million people in 56 countries
Our study evaluated the effect of the immune system in modulating the oviposition of worms and the expression of genes mainly related to epigenetic regulation in worms
We examined how methylation of liver DNA and the expression of related genes are influenced during Schistosoma mansoni infection depending on the type of immune response presented by the host
Summary
Schistosoma mansoni is a helminth parasite that causes schistosomiasis, a disease affecting about 200 million people in 56 countries. Most of the eggs remain trapped in different organs of the definitive host, such as the liver, provoking inflammatory response and hepatic fibrosis. Oviposition, granuloma size, and cytokine and interleukin types can be modulated depending on the host profile, and variation in the aggressiveness of infection may be related to adaptation mechanisms of the parasite to the immunological environment in which it is found. Granulomas from rodent infections from natural reservoirs are less aggressive in the liver and more aggressive in the intestine; the composition of the granuloma in these animals is characterized by the presence of extracellular matrix and fewer inflammatory cells [5]. Swiss strains infected with S. mansoni exhibit granulomas with extensive inflammatory infiltrates, often involving several eggs and the presence of necrosis [5]
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