Figure 1. Life cycle of T. gondii and factors with known contribution to stage conversion.
(A) Upon invasion of any nucleated host cell tachyzoites, bradyzoites or sporozoites form a parasitophorous vacuole surrounded by a membrane (PVM) and eventually multiply and disseminate as tachyzoites. In vitro, human foreskin fibroblasts are most frequently used for tachyzoite cultivation. The chronic bradyzoite stage forms in tissue cysts in the eye, brain, and muscle tissue. In vitro, bradyzoite formation is induced by various stresses (e.g., alkaline cell culture medium pH 8.3; see text for additional stressors). Overexpression of BFD1, BFD2/ROCY1, deletion of MORC or inhibition of HDAC3 induce bradyzoite formation in vitro. Bradyzoites can reactivate to tachyzoites, which is attenuated by elF2⍺ dephosphorylation inhibitors salubrinal (SAL) and guanabenz (GA)5. Several transcription factors of the Apetala 2 (AP2n) family are involved at various steps. (B) After ingestion of tissue cysts, bradyzoites invade the intestinal epithelium of intermediate hosts and differentiate to tachyzoites. These pass the intestinal epithelium and disseminate throughout the host. (C) Only in the intestinal epithelium of felines, where linoleic acid content is high due to a natural delta-6-desaturase (D6D) deficiency, can bradyzoites commence with the sexual developmental pathway. Merozoites replicate asexually, commit to a sexual fate, give rise to male and female gametocytes, eventually leading to oocyst formation. Further currently unknown factors (“?”) might be required. Similar conditions can be mimicked in mouse intestinal organoid-derived cells when D6D activity is inhibited and, in addition, linoleic acid is supplemented6. Inhibition of MORC or HDAC3 induce sexual stage-specific gene expression in tachyzoites (dashed line). (D) Eventually, oocysts are shed with the feline’s feces and sporulate in the environment under aerobic conditions. Oocysts are resistant to environmental stressors such as ultraviolet irradiation, salinity, high and low temperatures, and desiccation.