# Microglia sense fungal infections through capsular components from capillary-bound Cryptococcus neoformans via endothelial nucleotide signaling

## TL;DR

Microglia detect brain fungi through signals from blood vessels, not direct contact, which could lead to new treatments.

## Contribution

A novel mechanism is revealed where microglia sense fungal infections via endothelial nucleotide signaling.

## Key findings

- Microglia detect capillary-bound Cryptococcus neoformans before it crosses the blood-brain barrier.
- Glucuronoxylomannan activates endothelial cells to release nucleotides that trigger microglial responses.
- Microglial response promotes fungal growth rather than clearance.

## Abstract

Macrophages are essential for host defense, yet how parenchyma-residing macrophages detect pathogens without direct contact remains unclear. Cryptococcus neoformans is an encapsulated fungal pathogen that infects the brain. Using in situ imaging of mouse model, we showed that brain-resident microglia vigilantly detect capillary-residing C. neoformans prior to its blood–brain barrier transmigration, but are less responsive to nonencapsulated fungi or parenchyma-injected C. neoformans. Microglia migrate to and enwrap leaky capillaries harboring fungi, leading to fungal uptake but not clearance, instead promoting fungal growth. Microglial response is triggered by released capsule components, rather than the assembled capsule. In particular, glucuronoxylomannan (GXM) plays a critical role by activating endothelial cells to release nucleotides which act on microglia P2Y12. Our findings revealed a novel paradigm by which microglia detect pathogens without direct contact, offering new insights for microglia-directed antifungal therapies.

Brain macrophages detect pathogens without direct contact, yet how this occurs remains unclear. This study shows that microglia sense capsular components from capillary-bound Cryptococcus neoformans via endothelial nucleotide signaling, triggering uptake but not clearance.