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首页> 美国卫生研究院文献>Pathogens >Neospora caninum: Structure and Fate of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294
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Neospora caninum: Structure and Fate of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294

机译：新孢子虫：颠簸的激酶抑制剂BKI 1294诱导的多核复合物的结构和命运。

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Background: Bumped kinase inhibitors (BKIs) are potential drugs for neosporosis treatment in farm animals. BKI-1294 exposure results in the formation of multinucleated complexes (MNCs), which remain viable in vitro under constant drug pressure. We investigated the formation of BKI-1294 induced MNCs, the re-emergence of viable tachyzoites following drug removal, and the localization of CDPK1, the molecular target of BKIs. Methods: tachyzoites and MNCs were studied by TEM and immunofluorescence using antibodies directed against CDPK1, and against NcSAG1 and IMC1 as markers for tachyzoites and newly formed zoites, respectively. Results: After six days of drug exposure, MNCs lacked SAG1 surface expression but remained intracellular, and formed numerous zoites incapable of disjoining from each other. Following drug removal, proliferation continued, and zoites lacking NcSAG1 emerged from the periphery of these complexes, forming infective tachyzoites after 10 days. In intracellular tachyzoites, CDPK1 was evenly distributed but shifted towards the apical part once parasites were extracellular. This shift was not affected by BKI-1294. Conclusions: CDPK1 has a dynamic distribution depending on whether parasites are located within a host cell or outside. During MNC-to-tachyzoite reconversion newly formed tachyzoites are generated directly from MNCs through zoites of unknown surface antigen composition. Further in vivo studies are needed to determine if MNCs could lead to a persistent reservoir of infection after BKI treatment.
机译：背景：颠簸激酶抑制剂（BKIs）是用于农场动物新孢子虫病治疗的潜在药物。 BKI-1294暴露导致形成多核复合物（MNC），该复合物在恒定的药物压力下仍可在体外存活。我们调查了BKI-1294诱导的MNC的形成，药物去除后活性速殖子的重新出现以及BKIs的分子靶标CDPK1的定位。方法：使用针对CDPK1的抗体以及针对NcSAG1和IMC1的抗体分别通过TEM和免疫荧光研究速殖子和MNCs，作为速殖子和新形成的动物的标记。结果：暴露于药物的六天后，MNC缺乏SAG1表面表达，但仍在细胞内，并形成了许多不能彼此分离的动物。去除药物后，增殖继续，缺乏NcSAG1的动物从这些复合物的周围出现，在10天后形成感染性速殖子。在细胞内的速殖子中，CDPK1均匀分布，但一旦寄生虫进入细胞外，就会向顶端转移。此转移不受BKI-1294的影响。结论：CDPK1具有动态分布，取决于寄生虫位于宿主细胞内还是宿主细胞外。在从MNC到速殖子的转化过程中，新生成的速殖子是通过表面抗原组成未知的沸石直接从MNC生成的。需要进一步的体内研究来确定BNC治疗后MNC是否会导致持续的感染库。

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