Kent Robyn S, Ward Gary E
Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine, Burlington, Vermont, USA 05405.
1041 BMSB, Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190.
bioRxiv. 2024 Sep 28:2024.09.28.615543. doi: 10.1101/2024.09.28.615543.
The tachyzoite stage of the apicomplexan parasite utilizes motility for multiple purposes during its lytic cycle, including host cell invasion, egress from infected cells, and migration to new uninfected host cells to repeat the process. Bradyzoite stage parasites, which establish a new infection in a naïve host, must also use motility to escape from the cysts that are ingested by the new host and then migrate to the gut wall, where they either invade cells of the intestinal epithelium or squeeze between these cells to infect the underlying connective tissue. We know very little about the motility of bradyzoites, which we analyze in detail here and compare to the well-characterized motility and motility-dependent processes of tachyzoites. Unexpectedly, bradyzoites were found to be as motile as tachyzoites in a 3D model extracellular matrix, and they showed increased invasion into and transmigration across certain cell types, consistent with their need to establish the infection in the gut. The motility of the two stages was inhibited to the same extent by cytochalasin D and KNX-002, compounds known to target the parasite's actomyosin-based motor. In contrast, other compounds that impact tachyzoite motility (tachyplegin and enhancer 5) have less of an effect on bradyzoites, and rapid bradyzoite egress from infected cells is not triggered by treatment with calcium ionophores, as it is with tachyzoites. The similarities and differences between these two life cycle stages highlight the need to characterize both tachyzoites and bradyzoites for a more complete understanding of the role of motility in the parasite life cycle and the effect that potential therapeutics targeting parasite motility will have on disease establishment and progression.
顶复门寄生虫的速殖子阶段在其裂解周期中利用运动实现多种目的，包括侵入宿主细胞、从受感染细胞中逸出以及迁移到新的未感染宿主细胞以重复这一过程。缓殖子阶段的寄生虫在新宿主中建立新感染时，也必须利用运动从新宿主摄入的包囊中逸出，然后迁移到肠壁，在那里它们要么侵入肠上皮细胞，要么挤入这些细胞之间以感染下方的结缔组织。我们对缓殖子的运动了解甚少，在此我们对其进行详细分析，并与特征明确的速殖子运动及与运动相关的过程进行比较。出乎意料的是，在三维模型细胞外基质中发现缓殖子与速殖子的运动能力相当，并且它们对某些细胞类型的侵入和跨膜迁移有所增加，这与其在肠道中建立感染的需求一致。细胞松弛素D和KNX - 002这两种已知靶向寄生虫基于肌动球蛋白的运动蛋白的化合物，对这两个阶段的运动抑制程度相同。相比之下，其他影响速殖子运动的化合物（速动抑制剂和增强剂5）对缓殖子的影响较小，并且用钙离子载体处理不会像对速殖子那样触发缓殖子从受感染细胞中快速逸出。这两个生命周期阶段的异同凸显了对速殖子和缓殖子都进行特征描述的必要性，以便更全面地了解运动在寄生虫生命周期中的作用，以及针对寄生虫运动的潜在治疗方法对疾病发生和发展的影响。
