Análogos sintéticos de chalconas inibem a infecção por Toxoplasma gondii em células trofoblásticas humanas e explantes vilosos

Abstract

Congenital toxoplasmosis is an important public health problem worldwide caused by the transplacental passage of opportunistic protozoan parasite Toxoplasma gondii. The vertical transmission can lead to severe complications to embryo/fetus including miscarriages, stillbirth, growth restriction, malformations, neurological damage, encephalitis, chorioretinitis and brain calcifications. Once confirmed, the standard treatment consists in an association of sulfadiazine with pyrimethamine. However, these drugs have been linked to serious side effects, high toxicity and the development of drug resistant parasites, highlighting the urgent necessity for alternative therapeutics with less toxicity for mother and child. The current study showed that synthetic analogues of chalcones, compounds belonging to the flavonoid family, were capable to control the infection of T. gondii in both human trophoblast cells (BeWo) and placental human explants. Non-cytotoxic doses of C2, C4 and C9 impaired invasion and subsequent intracellular proliferation of parasite with an irreversible manner in BeWo cells. Scanning and transmission electron microscopies evidenced the direct effect of chalcones on tachyzoites, which presented irregular rough surface, membrane with hole-like structures, torsion and shape substantial changes after pretreatment. Also, C4 and, especially, C9 caused notable ultrastructural damages by the formation of vacuole-like structures in parasites cytoplasm and surrounding the parasitophorous vacuole. In addition, chalcones modulated cytokines profile, increasing IL-8 and downmodulatingROS in BeWo cells and upregulating TNF-α release in villous explants. Our findings reveled the potential of C2, C4 and C9 as alternative treatments for congenital toxoplasmosis as well as chalcones as a promising scaffold for new anti-T. gondii molecules design.