Mycophenolic acid induces differentiation of Toxoplasma gondii RH strain tachyzoites into bradyzoites and formation of cyst-like structure in vitro

Abstract

The biochemical and structural changes that occur during the conversion of Toxoplasma gondii tachyzoites to bradyzoites and the formation of tissue cyst are not well understood. Maintaining cells infected with T. gondii type II and III strains under stress conditions induces the tachyzoite-bradyzoite in vitro differentiation, along with the formation of cyst-like structures. However, due to the long exposure to such conditions required to induce the differentiation, the severe damages in the host cell and the low encystation frequency, it has been difficult to dissect in more detail these processes. Here, we successfully induced the in vitro formation of Toxoplasma cysts-like structures from tachyzoites of the type I RH strain by treating with mycophenolic acid, an inhibitor of the inosine monophosphate dehydrogenase. Mycophenolic acid is a drug widely used for HXGPRT positive selection of Toxoplasma mutant strains along with xanthine incubation in the culture medium; under such conditions, formation of tissue cysts has not been reported. We show that the exposure of extracellular tachyzoites to mycophenolic acid in absence of xanthine, followed by host cell invasion, triggered their differentiation into cyst-like structures. The differential expression of CST1, BAG1, and SAG1 molecules, as well as the structural modifications of infected cells, was characterized during the formation of cyst-like structures in vitro. These findings will allow the characterization of signaling pathways involved in tachyzoite to bradyzoite conversion and formation of tissue cysts.

Drug Repurposing Based on Protozoan Proteome: In Vitro Evaluation of In Silico Screened Compounds against Toxoplasma gondii

“…Mycophenolic acid is an antineoplastic antibiotic derived from various Penicillium fungal species. It was previously reported that this drug triggers T. gondii extracellular tachyzoites differentiation into cyst-like structures [53]. Fusidic acid, an antibiotic that inhibits the growth of bacteria by preventing the release of translation elongation factor G from the ribosome, has been shown to be effective in tissue culture against P. falciparum and T. gondii [54].…”

Changes in the Proliferation of the Neural Progenitor Cells of Adult Mice Chronically Infected with Toxoplasma gondii

“…These molecules and other molecular mechanisms not well characterized are involved in the differentiation of tachyzoites into bradyzoites and in the transformation of the host cells into tissue cysts [1,2]. Tissue cysts are located mostly in the brain and remain viable for the lifetime of the host and are responsible for chronic infections [3]. Interconversion from tachyzoites to bradyzoites residing into tissue cysts 2 of 14 is regulated by a multilayered cascade of steps involving promoter-based cis-elements, epigenetic modifications, and protein translation control through eukaryotic initiation factor-2 (eIF2) [4][5][6].…”

“…infections [3]. Interconversion from tachyzoites to bradyzoites residing into tissue regulated by a multilayered cascade of steps involving promoter-based cis-eleme genetic modifications, and protein translation control through eukaryotic initiation 2 (eIF2) [4][5][6].…”