Wu Xiao-Jing, Wang Meng, Zhang Nian-Zhang, Li Ting-Ting, Gao Jin, Sun Li-Xiu, Zhu Xing-Quan, Wang Jin-Lei
State Key Laboratory for Animal Disease Control and Prevention, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, People's Republic of China.
Laboratory of Parasitic Diseases, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, People's Republic of China.
FASEB J. 2025 Mar 31;39(6):e70476. doi: 10.1096/fj.202402593RR.
Cyst formation, resulting from the differentiation of rapidly replicating tachyzoites into slowly growing bradyzoites, is the primary cause of chronic toxoplasmosis. Although the mechanisms governing bradyzoite differentiation have been partially elucidated, they remain incompletely understood. In this study, we show that the transcription factor AP2XII-9 is localized in the nucleus and exhibits periodic expression during the tachyzoite stage, with peak expression observed during the synthesis and mitosis phases. Conditional knockdown of AP2XII-9 in both the type I RH strain and type II cyst-forming Pru strain revealed that AP2XII-9 plays a critical role in the lytic cycle by regulating the formation of the inner membrane complex, proper apicoplast inheritance, and normal cell division, underscoring its essential role in T. gondii growth. Furthermore, depletion of AP2XII-9 induced bradyzoite differentiation even in the absence of alkaline stress. Transcriptomic analysis revealed that the deletion of AP2XII-9 resulted in the downregulation of tachyzoite growth-related genes and upregulation of a series of bradyzoite-specific genes. Taken together, these findings indicate that AP2XII-9 is essential for maintaining the rapid and normal replication of tachyzoites while actively repressing bradyzoite differentiation, reflecting the complexity of the mechanisms underlying bradyzoite differentiation.
包囊形成是慢性弓形虫病的主要原因，它是由快速复制的速殖子分化为生长缓慢的缓殖子所致。尽管调控缓殖子分化的机制已部分阐明，但仍未完全了解。在本研究中，我们发现转录因子AP2XII-9定位于细胞核，并且在速殖子阶段呈现周期性表达，在合成期和有丝分裂期观察到表达峰值。在I型RH株和II型形成包囊的Pru株中对AP2XII-9进行条件性敲低，结果显示AP2XII-9通过调节内膜复合体的形成、正确的顶质体遗传和正常的细胞分裂，在裂解周期中发挥关键作用，突出了其在弓形虫生长中的重要作用。此外，即使在没有碱性应激的情况下，AP2XII-9的缺失也会诱导缓殖子分化。转录组分析显示，AP2XII-9的缺失导致速殖子生长相关基因下调以及一系列缓殖子特异性基因上调。综上所述，这些发现表明AP2XII-9对于维持速殖子的快速正常复制至关重要，同时积极抑制缓殖子分化，这反映了缓殖子分化潜在机制的复杂性。
