# Host Immune Cell Membrane Deformability Governs the Uptake Route of Malaria-Derived Extracellular Vesicles

## TL;DR

Malaria parasites use different methods to enter immune cells, depending on the cell's membrane properties.

## Contribution

This study reveals that membrane deformability, not just molecular interactions, determines how malaria-derived EVs are taken up by immune cells.

## Key findings

- T cells internalize EVs mainly through plasma membrane interaction, while monocytes use endocytosis.
- EV uptake depends on biophysical properties of the cell membrane, such as cholesterol content.
- The malaria parasite uses distinct communication tactics to target different immune cell types.

## Abstract

The malaria parasite, Plasmodium falciparum, secretes extracellular vesicles (EVs) to facilitate its growth
and to communicate with the external microenvironment, primarily targeting
the host’s immune cells. How parasitic EVs enter specific immune
cell types within the highly heterogeneous pool of immune cells remains
largely unknown. Using a combination of imaging flow cytometry and
advanced fluorescence analysis, we demonstrated that the route of
uptake of parasite-derived EVs differs markedly between host T cells
and monocytes. T cells, which are components of the adaptive immune
system, internalize parasite-derived EVs mainly through an interaction
with the plasma membrane, whereas monocytes, which function in the
innate immune system, take up these EVs via endocytosis. The membranal/endocytic
balance of EV internalization is driven mostly by the amount of endocytic
incorporation. Integrating atomic force microscopy with fluorescence
data analysis revealed that internalization depends on the biophysical
properties of the cell membrane rather than solely on molecular interactions.
In support of this, altering the cholesterol content in the cell membrane
tilted the balance in favor of one uptake route over another. Our
results provide mechanistic insights into how P. falciparum-derived EVs enter into diverse host cells. This study highlights
the sophisticated cell-communication tactics used by the malaria parasite.