# The role of inositol in Cryptococcus biology and pathogenesis

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $87,188

## Abstract

ABSTRACT
Cryptococcus neoformans is a deadly fungal pathogen that exhibits pronounced neurotropism: it is the most
common cause of fungal meningitis, particularly in immunocompromised patients, resulting in over 620,000
deaths annually. How C. neoformans cells traverse the blood-brain barrier (BBB) to infect the central nervous
system (CNS) remains poorly understood. Our recent studies implicate inositol – one of the most abundant
metabolites in the brain – in this process. In particular, we find that growth of C. neoformans under inositol-rich
conditions enhances fungal virulence and that fungal mutants defective in inositol uptake exhibit reduced
virulence, reduced capacity to transmigrate from the blood into the brain, and reduced ability to traverse a
model BBB in vitro. We also find that C. neoformans compromises tight-junction integrity in vitro, promoting
inositol leakage through the brain microvascular endothelial monolayer. Furthermore, we show that inositol
induces the expression of fungal cell surface factors involved in virulence, including the polysaccharide
capsule, a major fungal virulence factor, and hyaluronic acid (HA), a ligand important for fungal binding to the
BBB. Finally, we find that growth on inositol promotes the production of capsule structures involved in immune
evasion and that, conversely, C. neoformans mutants defective in inositol uptake elicit enhanced protective
immunity during brain infection. Based on these results, we hypothesize that C. neoformans senses and
utilizes host inositol to modify the fungal cell surface in a way that promotes penetration of the BBB and
development of cryptococcal meningitis. Interestingly, C. neoformans contains an unusually complex inositol
uptake system and catabolic pathway, which likely evolved from its utilization of the inositol stores of its plant
reservoirs. Thus, this fungus may be uniquely adapted to thrive in the inositol-rich environment of the CNS and
to utilize inositol-dependent pathways for pathogenesis. The overarching goal of this proposal is to obtain a
detailed understanding of the mechanism by which C. neoformans acquires and utilizes host inositol to
establish human brain infection. We propose three Specific Aims: 1) Define inositol sensing and metabolic
pathways required for modifying fungal cell surface structure by using a combination of fungal mutagenesis
analysis, enzymatic assays, and polysaccharide structural analysis; 2) Characterize the mechanism of inositol
promotion in C. neoformans BBB crossing and CNS infection by using an in vitro BBB model system and in
vivo animal models; and 3) Define the transcriptional circuits regulating inositol-dependent processes during
cryptococcal brain infection by analyzing the expression and localization of fungal inositol factors and
identifying transcription factors regulating their expression during infection. Together, these studies will
elucidate a novel contribution of a brain metabolite, inositol, to the dev...

## Key facts

- **NIH application ID:** 9903576
- **Project number:** 3R01AI123315-04S1
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Chaoyang Xue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $87,188
- **Award type:** 3
- **Project period:** 2016-11-24 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903576

## Citation

> US National Institutes of Health, RePORTER application 9903576, The role of inositol in Cryptococcus biology and pathogenesis (3R01AI123315-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9903576. Licensed CC0.

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