Effects And Mechanism Of Estradiol And Progesterone On Toxoplasma Gondii Infection

Host species of Toxoplasma gondii are extremely widespread.As an opportunistic pathogen,Toxoplasma gondii is more susceptible to pregnant females,and causes reproductive disorders.Dramatic changes of estrogen levels during pregnancy may be an important factor for high infectivity and pathogenicity of Toxoplasma in this period.Therefore,we selected estradiol and progesterone which have significantly increased levels during pregnancy to clarify the effects of the two hormones on T.gondii infection and pathogenicity.Our results showed that estradiol could promote the invasion of Pru and VEG strains into various host cells,and estrogen antagonists suppressed this effect,suggesting that there must be some effectors interacted with estradiol in T.gondii.Subsequently,we found that estradiol enhanced the pathogenicity of T.gondii in mice.Further studies revealed that estradiol could enter the cytoplasm of parasites and rapidly induce intracellular calcium flux through PI-PLC and PKG pathways.This effect promoted the secretion of Tg-MIC2,and enhanced the gliding and egress abilities of parasites,thereby affected the parasites invasion,proliferation,and pathogenicity in mice.In addition,we found a sex hormone metabolism gene Tg-HSD in the T.gondii genome.Tg-HSD can metabolize estrone to estradiol.Overexpression of Tg-HSD significantly increased the level of estradiol in infected mice,and it indeed enhanced pathogenicity of parasites in mice,mimicking the phenotypes observed in the treatment with estradiol.Progesterone failed to promote the invasion of T.gondii,and significantly inhibited the growth of parasites.Progesterone also reduced the pathogenicity of T.gondii in mice.Although progesterone induced intracellular calcium release and promoted the egress of T.gondii,it inhibited the secretion of Tg-MIC2,and reduced gliding ability to downregulate the pathogenicity of parasites.Meanwhile,T.gondii cultured with progesterone showed abnormal division,disordered formation of inner membrane complex,and aggregation of Tg-ATG8 autophagy protein,which eventually induced apoptosis of T.gondii.Subsequently,we found a progesterone membrane receptor Tg-PGRMC in T.gondii.Knockout of the gene encoding this receptor had no influence on the growth of parasites,but suppressed the inhibitory effects of progesterone on T.gondii.In addition,knockout of the gene in Pru strain(type II)reduced the pathogenicity of T.gondii in mice.Based on the above studies,we found that Tg-PGRMC interacted with Tg-P450,and Tg-P450 was unnecessary for the growth of T.gondii,but overexpressing Tg-P450 enhanced the pathogenicity of parasites in mice.In addition,we demonstrated that Tg-P450 had weak enzyme activities,similar to mammalian CYP3A and CYP2B.This function made T.gondii able to resist the killing effects of exogenous drugs.Progesterone reduced Tg-P450 expression and enzyme activities to reduce the resistance of parasites to exogenous drugs.In this study,we tried to dissect the possible relationship between the hormones relevant to pregnancy and the pathogenesis of T.gondii,and found their opposite effects of hormones on the T.gondii pathogenesis,by mainly acting on the secretion of MIC2 and parasite motility.Subsequently,the progesterone membrane receptor Tg-PGRMC of T.gondii was identified and related to progesterone-induced parasites growth inhibition.Meanwhile,we found that progesterone can reduce the resistance of T.gondii to negative factors by inhibiting the activity of Tg-P450.