Gelli, A. | Search bioRxiv

bioRxiv2025

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

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 for CD44, 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.

molecular biology↗

bioRxiv2022

Characterization of the growth and morphology of a BSL-2 Coccidioides posadasii strain that persists in the parasitic life cycle at ambient CO2.

Coccidioides is a dimorphic fungus responsible for Valley Fever and is the cause of severe morbidity and mortality in the infected population. Although there is some insight into the genes, pathways, and growth media involved in the parasitic to saprophytic growth transition, the exact determinants that govern this switch are largely unknown. In this work, we examined the growth and morphology of a novel Coccidioides posadasii strain (C. posadasii S/E) that efficiently produces spherules and endospores and persists in the parasitic life cycle at ambient CO2. We demonstrated that C. posadasii S/E remains virulent in an insect infection model. Surprisingly, under spherule-inducing conditions, C. posadasii S/E culture was found to be completely hyphal. Differential interference contrast (DIC) and transmission electron microscopy (TEM) revealed unexpected cellular changes in this strain including cell wall remodeling and formation of septal pores with Woronin bodies. Our study suggests that the C. posadasii S/E strain is a useful BSL-2 model for studying the molecular factors that are active during the parasitic life cycle and the mechanisms underlying the parasitic to saprophytic growth transition - a morphological switch that can impact the pathogenicity of the organism in the host.

microbiology↗