# Macropinocytosis mediates neurotropism of Cryptococcus neoformans in a human organoid model of the blood-brain barrier

## TL;DR

This study shows how the fungus Cryptococcus neoformans enters brain cells using a process called macropinocytosis, which could help develop better treatments for brain infections.

## Contribution

The paper identifies CD44 and EphA2 as key proteins involved in the fungal entry mechanism into brain endothelial cells via macropinocytosis.

## Key findings

- Cryptococcus neoformans uses macropinocytosis to enter brain endothelial cells.
- CD44 and EphA2 form a molecular complex that facilitates fungal entry.
- Two predicted binding sites on EphA2 suggest cooperative signaling for macropinocytosis.

## Abstract

The opportunistic and neuroinvasive fungus, Cryptococcus neoformans (Cn), causes a life-threatening brain infection that despite treatment can cause long-term cognitive deficiencies. Studies have shown that Cn can infiltrate the central nervous system (CNS) through a transcellular route across the brain endothelium, however the molecular process that drives brain endothelial cells to internalize Cn remains poorly defined. Here we examine the molecular interactions between fungal cells and the brain endothelium by utilizing a human 3D organoid model of the blood-brain barrier (BBB). We show that Cn exploits the process of macropinocytosis as the mechanism of endocytosis into brain endothelial cells by recruiting CD44 and EphA2 as a molecular complex. We identified two predicted binding sites on EphA2, suggesting that the two structurally distinct regions may provide a molecular basis for cooperative signaling in brain endothelial cells that stimulate macropinocytosis as the mode of entry for Cn.