Malaria parasites harness Rho GTPase signaling and host cell membrane ruffling for productive invasion of hepatocytes

Plasmodium sporozoites are the motile forms of the malaria parasites that infect hepatocytes. The initial invasion of hepatocytes is thought to be actively driven by sporozoites, but host cell processes might also play a role. Sporozoite invasion triggers a host plasma membrane invagination that forms a vacuole around the intracellular parasite, which is critical for subsequent intracellular parasite replication. Using fast live confocal microscopy, we observed that the initial interactions between sporozoites and hepatocytes induce plasma membrane ruffles and filopodia extensions. Importantly, we find that these host cell processes facilitate invasion and that Rho GTPase signaling, which regulates membrane ruffling and filopodia extension, is critical for productive infection. Interestingly, sporozoite cell traversal stimulates these processes, suggesting that it increases hepatocyte susceptibility to productive infection. Our study identifies host cell signaling events involved in plasma membrane dynamics as a critical host component of successful malaria parasite infection of hepatocytes.