# The role of inositol in Cryptococcus biology and pathogenesis

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $703,427

## Abstract

ABSTRACT
Cryptococcus neoformans (Cn) is the most common cause of fungal meningoencephalitis, a life-threatening
disease. Despite extensive efforts, the mechanism whereby Cn crosses the blood-brain barrier (BBB) and
causes meningitis remains poorly understood. Our previous study discovered that inositol, a host sugar
metabolite highly abundant in the brain, promotes fungal traversal of the BBB and plays a critical role in host-
pathogen interactions during infection of the central nervous system (CNS). In our previous funding period, we
have demonstrated that Cn contains an unusually complex inositol uptake system that is distinct from those
characterized in other fungi. Thus, Cn may be uniquely adapted to thrive in the inositol-rich environment of the
CNS and to utilize inositol-dependent pathways for pathogenesis. Our data have confirmed that (1) growth of Cn
under inositol-rich conditions enhanced virulence in the murine model, (2) fungal cells deficient in inositol uptake
and catabolism were also deficient in virulence during CNS infection, (3) inositol induced production of fungal
capsule, a major virulence factor, and hyaluronic acid, a cell surface molecule involved in fungal binding to the
BBB, and (4) inositol induced a unique capsule structure enriched in a specific mannosylated structure group
that helps the fungus evade the host immune response. We also identified an inositol receptor Itr4 and a
transcription factor Hlh6 that are required for inositol function in Cn. Our central hypothesis is that cryptococcal
cells sense and utilize host inositol to modify the fungal cell surface in a way that promotes penetration of the
BBB and development of cryptococcal meningoencephalitis. The overarching goal of this proposal is to
understand how this pathogen senses and utilizes host nutrient inositol to establish human brain infections. To
further test our hypothesis, we propose two related but independent Specific Aims: 1) Characterize Inositol
mediated fungal cell surface modification in Cryptococcus-host interaction using genetics, molecular biology and
biophysical approaches in combination of in vitro BBB system and in vivo animal models. Fungal strains with
single motif capsule structure will be utilized for this study. 2) Define the inositol sensing and regulatory
mechanism important for fungal pathogenesis by characterizing the inositol sensor Itr4 and inositol transcription
factors and the pathways they regulated. Moreover, we will test a number of inhibitors on inositol function for
their potential antifungal activity to explore the possibility to develop the fungal inositol function as a potential
therapeutic target. The proposed study will provide a mechanistic understanding of inositol utilization in Cn and
its effects on fungal pathogenesis, especially during CNS infections.

## Key facts

- **NIH application ID:** 10994396
- **Project number:** 2R01AI123315-06A1
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Chaoyang Xue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $703,427
- **Award type:** 2
- **Project period:** 2016-11-24 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994396

## Citation

> US National Institutes of Health, RePORTER application 10994396, The role of inositol in Cryptococcus biology and pathogenesis (2R01AI123315-06A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10994396. Licensed CC0.

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