Electron tomography of Plasmodium falciparum merozoites reveals core cellular events that underpin erythrocyte invasion

Summary Erythrocyte invasion by merozoites forms of the malaria parasite is a key step in the establishment of human malaria disease. To date, efforts to understand cellular events underpinning entry have been limited to insights from non‐human parasites, with no studies at sub‐micrometer resolution undertaken using the most virulent human malaria parasite, Plasmodium falciparum. This leaves our understanding of the dynamics of merozoite sub‐cellular compartments during infectionincomplete, in particular that of the secretory organelles. Using advances in P. falciparum merozoite isolation and new imaging techniques we present a three‐dimensional study of invasion using electron microscopy, cryo‐electron tomography and cryo‐X‐ray tomography. We describe the core architectural features of invasion and identify fusion between rhoptries at the commencement of invasion as a hitherto overlooked event that likely provides a critical step that initiates entry. Given the centrality of merozoite organelle proteins to vaccine development, these insights provide a mechanistic framework to understand therapeutic strategies targeted towards the cellular events of invasion. Invasion of the human erythrocyte by Plasmodium parasites is critical for establishment of malaria disease. Over several decades researchers have developed a detailed molecular map of events underpinning invasion, however, cellular understanding of entry by P. falciparum – the parasite responsible for most mortality from malaria – has remained limited. In this issue, Hanssen and Dekiwadia et al. address this shortcoming, presenting the first 3D study of invasion using state‐of‐the‐art electron microscopy to reveal high‐definition insights into this key step in parasite biology.