Resveratrol induces H2A.X phosphorylation and H4K16 de-acetylation in Toxoplasma gondii

Resveratrol (RSV) is a multi-target drug that demonstrated activity against Toxoplasma gondii in macrophage and HFF cell line infection models. In addition to modulate redox homeostasis, RSV is also an activator of Sir2, a type III HDAC. RSV inhibited intracellular T. gondii tachyzoite growth at concentrations below the toxic effect on host cells. The IC50 value in a 24-hours treatment was 53 M. After 96 hours of treatment the maximum non-toxic concentration for host cell, 20 M, only inhibited T. gondii growth a 50%. RSV induced a reduction in H4K16 acetylation (H4K16ac), a mark associated to transcription, DNA replication and homologous recombination repair, without any effect on H3 acetylation (H3ac). RSV also enhanced the SQE motif phosphorylation on T. gondii H2A.X (termed {gamma}H2A.X), a DNA damage associated PTM. Sirtinol, a specific Sir2 inhibitor also inhibited T. gondii but did not altered the acetylation status of H3 and H4K16 as well as H2A.X phosphorylation. Our findings suggest a possible link between RSV and DNA damage or DNA repair process maybe due to DNA replication stress and/or another undetermined mechanism.