Constitutive upregulation of transcription factors underlies permissive bradyzoite differentiation in a natural isolate of .

Unlabelled: bradyzoites play a critical role in pathology due to their long-term persistence in intermediate hosts and their potential to reactivate, resulting in severe diseases in immunocompromised individuals. Currently, there is no effective treatment for eliminating bradyzoites. Hence, better models of bradyzoite development would facilitate identification of therapeutic targets for bradyzoites. Herein, we characterized a natural isolate of , called Tg68, which showed slower replication of tachyzoites, and permissive bradyzoite development under stress conditions . Transcriptional analysis revealed constitutive expression in Tg68 tachyzoites of the key regulators of bradyzoite development including , , and several AP2 factors. Consistent with this finding, Tg68 tachyzoites expressed high levels of bradyzoite-specific genes including , , and . Moreover, after stress-induced differentiation, Tg68 bradyzoites exhibited gene expression profiles of mature bradyzoites, even at early time points. These data suggest that Tg68 tachyzoites exist in a pre-bradyzoite stage primed to readily develop into mature bradyzoites under stress conditions . Tg68 presents a novel model for differentiation that will serve as a useful tool for the investigation of bradyzoite biology and the development of therapeutics.

Importance: is a widespread protozoan that chronically infects ~30% of the world's population. can differentiate between the fast-growing life stage that causes acute infection and the slow-growing stage that persists in the host for extended periods of time. The slow-growing stage cannot be eliminated by the host immune response or currently known antiparasitic drugs. Studies on the slow-growing stage have been limited due to the limitations of experiments and the challenges of manipulation. Here, we characterize a natural isolate of , which constitutively expresses factors that drive development and that is permissive to convert to the slow-growing stage under stress conditions . The strain presents a novel model for studying the chronic phase of toxoplasmosis and identifying new therapeutic treatments for chronic infections.