Novel roles of dense granule protein 12 (GRA12) in Toxoplasma gondii infection
Novel roles of dense granule protein 12 (GRA12) in Toxoplasma gondii infection
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致密颗粒蛋白12（GRA12）在弓形虫感染中的新作用
DOI：
10.1096/fj.201901416rr
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发表时间：
2020-01-06
期刊：
影响因子：
4.8
通讯作者：
Zhu, Xing-Quan
中科院分区：
文献类型：
--
作者：
Wang, Jin-Lei;Bai, Meng-Jie;Zhu, Xing-Quan
致密颗粒蛋白12（Dense granule protein 12，GRA 12）参与了弓形虫感染的一系列过程，如寄生虫空泡（PV）内空泡内网络（intravacuolar network，IVN）的形成。这种蛋白质也被认为对T.弓形虫-宿主相互作用、发病机制和免疫逃避，但其确切作用仍不清楚。本研究探讨了GRA 12在T.在体外和体内检测弓形虫感染。I型RH和II型Pru T中GRA 12的缺失。弓形虫株在体外不影响寄生虫的生长和复制，但在体内引起寄生虫毒力和组织包囊负荷的显著降低。T.弓形虫Δ gra 12突变体更容易被宿主免疫消除，而不会在PV膜上积累免疫相关的GTca 6（Irga 6）。在Δ gra 12突变体中，IVN的超微结构表现正常，表明GRA 12不是IVN生物发生所必需的。与单一Δ gra 12或Δ rop 18突变株相比，GRA 12和ROP 18的组合缺失诱导更严重的毒力衰减。这些数据表明GRA 12和ROP 18之间的功能关联，其通过双突变体相对于单个突变体中毒力的严重衰减来揭示。未来的研究需要确定这种假定的关联的分子基础。这些结果表明，尽管GRA 12对体外寄生虫的生长和复制不是必需的，但它有助于T.小鼠弓形虫感染
Dense granule protein 12 (GRA12) is implicated in a range of processes related to the establishment of Toxoplasma gondii infection, such as the formation of the intravacuolar network (IVN) within the parasitophorous vacuole (PV). This protein is also thought to be important for T. gondii‐host interaction, pathogenesis, and immune evasion, but their exact roles remain unknown. In this study, the contributions of GRA12 to the molecular pathogenesis of T. gondii infection were examined in vitro and in vivo. Deletion of GRA12 in type I RH and type II Pru T. gondii strains did not affect the parasite growth and replication in vitro, however, it caused a significant reduction in the parasite virulence and tissue cyst burden in vivo. T. gondii Δgra12 mutants were more vulnerable to be eliminated by host immunity, without the accumulation of immunity‐related GTPase a6 (Irga6) onto the PV membrane. The ultrastructure of IVN in Δgra12 mutants appeared normal, suggesting that GRA12 is not required for biogenesis of the IVN. Combined deletion of GRA12 and ROP18 induced more severe attenuation of virulence compared to single Δgra12 or Δrop18 mutant strains. These data suggest a functional association between GRA12 and ROP18 that is revealed by the severe attenuation of virulence in a double mutant relative to the single individual mutations. Future studies are needed to define the molecular basis of this putative association. Collectively these findings indicate that although GRA12 is not essential for the parasite growth and replication in vitro, it contributes to the virulence and growth of T. gondii in mice.