Identification of a Master Regulator of Differentiation in Toxoplasma

Toxoplasma gondii chronically infects a quarter of the world’s population, and its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent. Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies. The molecular basis of this differentiation is unknown, despite being efficiently triggered by stresses in culture. Through Cas9-mediated screening and single-cell profiling, we identify a Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice. BFD1 accumulates during stress and its synthetic expression is sufficient to drive differentiation. Consistent with its function as a transcription factor, BFD1 binds the promoters of many stage-specific genes and represents a counterpoint to the ApiAP2 factors that dominate our current view of parasite gene regulation. BFD1 provides a genetic switch to study and control Toxoplasma differentiation and will inform prevention and treatment of chronic infections. [Display omitted] •BFD1 is a master regulator of chronic-stage differentiation in Toxoplasma gondii•ΔBFD1 parasites fail to differentiate in cell culture or form cysts in infected mice•Conditional expression of BFD1 is sufficient to induce differentiation•BFD1 binds transcriptional start sites of genes induced during chronic stages A single parasite transcription factor drives the differentiation of Toxoplasma to a cyst-forming stage to sustain chronic infection.