Department of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Bioengineering, James H. Clark Center, Stanford University, Stanford, California, USA.
mBio. 2024 Apr 10;15(4):e0286423. doi: 10.1128/mbio.02864-23. Epub 2024 Mar 8.
Intracellular infectious agents, like the malaria parasite, , face the daunting challenge of how to invade a host cell. This problem may be even harder when the host cell in question is the enucleated red blood cell, which lacks the host machinery co-opted by many pathogens for internalization. Evolution has provided and related single-celled parasites within the phylum Apicomplexa with a collection of organelles at their apical end that mediate invasion. This apical complex includes at least two sets of secretory organelles, micronemes and rhoptries, and several structural features like apical rings and a putative pore through which proteins may be introduced into the host cell during invasion. We perform cryogenic electron tomography (cryo-ET) equipped with Volta Phase Plate on isolated and vitrified merozoites to visualize the apical machinery. Through tomographic reconstruction of cellular compartments, we see new details of known structures like the rhoptry tip interacting directly with a rosette resembling the recently described rhoptry secretory apparatus (RSA) or with an apical vesicle docked beneath the RSA. Subtomogram averaging reveals that the apical rings have a fixed number of repeating units, each of which is similar in overall size and shape to the units in the apical rings of tachyzoites of . Comparison of these polar rings in and parasites also reveals them to have a structurally conserved assembly pattern. These results provide new insight into the essential and structurally conserved features of this remarkable machinery used by apicomplexan parasites to invade their respective host cells.
Malaria is an infectious disease caused by parasites of the genus and is a leading cause of morbidity and mortality globally. Upon infection, parasites invade and replicate in red blood cells, where they are largely protected from the immune system. To enter host cells, the parasites employ a specialized apparatus at their anterior end. In this study, advanced imaging techniques like cryogenic electron tomography (cryo-ET) and Volta Phase Plate enable unprecedented visualization of whole merozoites, revealing previously unknown structural details of their invasion machinery. Key findings include new insights into the structural conservation of apical rings shared between and its apicomplexan cousin, . These discoveries shed light on the essential and conserved elements of the invasion machinery used by these pathogens. Moreover, the research provides a foundation for understanding the molecular mechanisms underlying parasite-host interactions, potentially informing strategies for combating diseases caused by apicomplexan parasites.
细胞内传染性病原体，如疟原虫，面临着如何入侵宿主细胞的艰巨挑战。当涉及到去核的红细胞时，这个问题可能更加困难，因为红细胞缺乏许多病原体用于内化的宿主机制。进化为单细胞寄生虫和相关的门 Apicomplexa 在它们的顶端提供了一组细胞器，用于入侵。这个顶端复合物至少包括两套分泌细胞器，微线体和棒状体，以及几个结构特征，如顶端环和一个推测的孔，通过这个孔，蛋白质可能在入侵过程中被引入宿主细胞。我们使用配备有 Volta 相板的低温电子断层扫描（cryo-ET）对分离和玻璃化的裂殖子进行成像，以可视化顶端机制。通过细胞区室的断层重建，我们看到了已知结构的新细节，如棒状体尖端与类似于最近描述的棒状体分泌器（RSA）的玫瑰花结直接相互作用，或与停靠在 RSA 下方的顶端囊泡相互作用。亚断层平均揭示了顶端环具有固定数量的重复单元，每个单元在整体大小和形状上都与速殖子的顶端环中的单元相似。比较 和 寄生虫的这些极性环也揭示了它们具有结构保守的组装模式。这些结果为 Apicomplexa 寄生虫用于入侵各自宿主细胞的这种非凡机制的基本和结构保守特征提供了新的见解。
疟疾是一种由 属寄生虫引起的传染病，是全球发病率和死亡率的主要原因。感染后， 寄生虫侵入并在红细胞中复制，在那里它们在很大程度上免受免疫系统的影响。为了进入宿主细胞，寄生虫在前部使用一种特殊的装置。在这项研究中，低温电子断层扫描（cryo-ET）和 Volta 相板等先进成像技术使整个 裂殖子的可视化成为可能，揭示了它们入侵机制的先前未知的结构细节。主要发现包括 属和它的 Apicomplexa 表亲之间顶端环结构保守性的新见解。这些发现揭示了这些病原体使用的入侵机制的基本和保守元素。此外，该研究为理解寄生虫-宿主相互作用的分子机制提供了基础，可能为对抗 Apicomplexa 寄生虫引起的疾病提供策略。
