Sialylated <i>N</i>‐glycans mediate monocyte uptake of extracellular vesicles secreted from <i>Plasmodium falciparum</i>‐infected red blood cells

Abstract

Glycoconjugates on extracellular vesicles (EVs) play a vital role in internalization and mediate interaction as well as regulation of the host immune system by viruses, bacteria, and parasites. During their intraerythrocytic life-cycle stages, malaria parasites, <i>Plasmodium falciparum</i> (<i>Pf</i>) mediate the secretion of EVs by infected red blood cells (RBCs) that carry a diverse range of parasitic and host-derived molecules. These molecules facilitate parasite-parasite and parasite-host interactions to ensure parasite survival. To date, the number of identified <i>Pf</i> genes associated with glycan synthesis and the repertoire of expressed glycoconjugates is relatively low. Moreover, the role of <i>Pf</i> glycans in pathogenesis is mostly unclear and poorly understood. As a result, the expression of glycoconjugates on <i>Pf</i>-derived EVs or their involvement in the parasite life-cycle has yet to be reported. Herein, we show that EVs secreted by <i>Pf</i>-infected RBCs carry significantly higher sialylated complex <i>N</i>-glycans than EVs derived from healthy RBCs. Furthermore, we reveal that EV uptake by host monocytes depends on N-glycoproteins and demonstrate that terminal sialic acid on the <i>N</i>-glycans is essential for uptake by human monocytes. Our results provide the first evidence that <i>Pf</i> exploits host sialylated <i>N</i>-glycans to mediate EV uptake by the human immune system cells.