# The molecular basis for the translocation of fungi from blood-to-brain.

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $348,877

## Abstract

PROJECT ABSTRACT
Infections of the central nervous system (CNS) caused by fungi have the highest morbidity and
mortality when compared to other causative agents of CNS infections. Cryptococcus neoformans
(Cn), Candida albicans, Aspergillus spp., Mucor, Coccidioides spp., and Histoplasma capsulatum
are the most common cause of fungal brain infections resulting in a chronic instead of an acute
or subacute meningoencephalitis. The long-term goal will investigate the spatio-temporal
organization and molecular basis of Cn trafficking across the BBB and investigate a cross-talk
between a transcellular mechanism and the opening of a paracellular path in response to Cn
infection. Given our preliminary data and published studies, we propose that Cn represents an
excellent model pathogen with which to determine the mechanisms that pathogenic fungi use to
breach the BBB and enter the CNS. In our efforts to understand the molecular basis mediating
the Cn-brain endothelium interactions, we identified a tyrosine kinase receptor (EphA2-TKR) as
the central player. The central hypothesis states that fungal cells penetrate the BBB by engaging
EphA2-TKR in order to access a binary path into the CNS. To test our hypothesis, we will
investigate the interplay between fungal cells, EphA2-TRK and its downstream signaling
components in mediating the translocation of Cn from blood-to-brain. The following specific aims
will test the hypothesis: SA1 will investigate a Cn-induced CD44-mediated transactivation of
EphA2-TKR activity and the interactome of EphA2-TKR. SA2 will examine the role of EphA2-TKR
in upregulating vesicular traffic of Cn and resolve whether Cn-induced activity of EphA2-TKR
promotes a co-regulation of a transcellular and paracellular pathway. SA3 will resolve the
contribution of EphA2-TKR activity to the translocation of Cn from blood-to-brain in vivo and
examine the molecular basis of changes in the permeability of the BBB when challenged by Cn.
The proposed research is innovative because it will for the first time, detail the key players that
promote the internalization and trafficking of fungi across the BBB. The innovation extends to our
published studies that identified EphA2-TKR in the brain endothelium as a central element in
mediating the migration Cn from blood-to-brain. This along with the notion that crossing of the
BBB is initiated by a fungal-induced CD44-transactivation of EphA2-TKR to trigger a pathological
use of endocytosis (and possibly a secondary paracellular path) in brain endothelial cells is a
paradigm shift from our current understanding. We have proposed experiments that will use
multiple complementary approaches to tease apart the molecular interaction between Cn, EphA2-
TKR and CD44 while also using proximity-dependent labeling to identify the interactome of
EphA2-TKR. The knowledge gained from our studies will make a significant contribution to fungal
pathogenesis of the CNS, because it remains significantly understudied, and t...

## Key facts

- **NIH application ID:** 9971167
- **Project number:** 1R01NS110800-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** ANGIE GELLI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,877
- **Award type:** 1
- **Project period:** 2020-04-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971167

## Citation

> US National Institutes of Health, RePORTER application 9971167, The molecular basis for the translocation of fungi from blood-to-brain. (1R01NS110800-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971167. Licensed CC0.

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