Identification of a Master Regulator of Differentiation in Toxoplasma

Abstract

Graphical AbstractHighlights d BFD1 is a master regulator of chronic-stage differentiation in Toxoplasma gondii d DBFD1 parasites fail to differentiate in cell culture or form cysts in infected mice d Conditional expression of BFD1 is sufficient to induce differentiation d BFD1 binds transcriptional start sites of genes induced during chronic stages SUMMARY 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.

One gene to rule them all in a chronic brain infection

“…The discovery could aid the design of therapies to eliminate this currently untreatable infection. 3 report that the gene BDF1 is required for this differentiation step. In both the acute and chronic stages of infection, this gene is transcribed into messenger RNA.…”

“…This lack of understanding of orphan Gproteincoupled receptors (oGPCRs) impedes our ability to exploit their potential as therapeutic targets. On page 152, Lin et al 3 close this gap in knowl edge by reporting the first 3D structure of a fulllength oGPCR, GPR52, in multiple states.…”

“…In their initial stud ies, the authors used a variety of strategies, including extensive protein engineering, to both stabilize the receptor and enable its production in sufficient quantities to pro duce highresolution crystal structures. The 3 report structures of the membrane receptor GPR52, a potential drug target for which the putative naturally occurring agonist -the ligand molecule that activates the receptor -is unknown. The authors find that a region of GPR52 known as extracellular loop 2 (ECL2) binds to a site in the receptor that is analogous to the agonistbinding site in other receptors from the same family.…”

“…The para site needs to differentiate into a chronicstage form to establish a permanent infection in brain and muscle tissue, but how this parasite conversion occurs has been a mystery. Writing in Cell, Waldman et al 3 report the identification of a gene that encodes a master regulator of this differentiation event.…”

Trypanosoma cruziamastigotes have a reduced replication rate during chronic stage infections

“…2019), the ‘dormant’ state involves lower levels of DNA synthesis and transcription, down-regulation of energy catabolism, and activation of DNA damage/cellular stress responses. In T. gondii , a master transcription factor (BFD1), activated by stress response pathways, initiates the on-set of bradyzoite development (Waldman et al . 2020).…”