The recrudescence of Toxoplasma cysts is the cause of clinical disease in the immunocompromised. Although Toxoplasma has been a useful parasite model for decades because it is relatively easy to genetically modify and culture, attempts to generate and study the recrudescence of tissue cysts have come up short with cell culture-adapted strains generating low numbers of tissue cysts in vivo. Taking advantage of a new ex vivo model of Toxoplasma recrudescence that uses a Type II ME49 strain unadapted to cell culture, we determined the cell biology, gene expression, and host cell dependency that define bradyzoite-cyst reactivation. Bradyzoite infection of fibroblasts and astrocytes produced sequential tachyzoite growth stages with pre-programmed kinetics; thus, an initial fast-growing stage was followed by a slow-growing replicating form. In vivo infections demonstrated that only fast growth tachyzoites, and not parasites post-growth shift, led to successful parasite dissemination to the brain and peripheral organs. In astrocytes, cells that reside in the central nervous system (CNS), bradyzoites initiated an additional recrudescent pathway involving brady-brady replication, which is a pathway not observed in fibroblasts. To investigate the molecular basis of growth and cell-dependent reactivation pathways, single-cell mRNA sequencing was performed on recrudescing parasites, revealing distinct gene signatures of these parasite populations and confirming multifunctionality of the original ex vivo bradyzoite population. This revised model of Toxoplasma recrudescence uncovers previously unknown complexity in the clinically important bradyzoite stage of the parasite, which opens the door to further study these novel developmental features of the Toxoplasma intermediate life cycle.
CITATION STYLE
Vizcarra, E. A., Goerner, A. L., Ulu, A., Hong, D. D., Bergersen, K. V., Talavera, M. A., … White, M. W. (2023). An ex vivo model of Toxoplasma recrudescence reveals developmental plasticity of the bradyzoite stage. MBio, 14(5). https://doi.org/10.1128/mbio.01836-23
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