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

  • PLoS Biol. 2026 Feb 6;24(2):e3003642. doi: 10.1371/journal.pbio.3003642.
Chenxu Feng  1 ,  Ge Wang  1  2 ,  Yixuan Wang  1 ,  Xiang Gao  1 ,  Zhenqi Xu  1  2 ,  Luyao Fang  2 ,  Ziyi Ma  1 ,  Suwei Zheng  1 ,  Yuyan Xie  3 ,  Yufeng Chu  1 ,  Mei Meng  1 ,  Angela Yang  1 ,  Miriam Lu  1 ,  Judd Denzel Garcia Mondina  1 ,  Weiwei Zhu  1 ,  Lisheng Zhang  2 ,  Linqi Wang  3 ,  Zongyan Chen  2 ,  Donglei Sun  1  4
Affiliations
  • 1. Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 2. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China.
  • 3. State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • 4. Shanghai Key Laboratory for Antibody-Drug Conjugates with Innovative Target, Shanghai, China.
PMID: 41650189 DOI: 10.1371/journal.pbio.3003642
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.

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