# Defining the genetic network governing cryptococcal morphological transition

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2023 · $471,846

## Abstract

Abstract
 Cryptococcal meningitis is an AIDS-defining condition and it is responsible for 15% of the deaths in
AIDS patients. The disease has mortality rates up to 70% and it claims hundreds of thousands of lives each
year. The existing antifungal drugs are not always effective and there is no vaccine available against
cryptococcosis. The challenges of preventing and treating this disease motivate us to investigate cryptococcal
pathogenesis and identify cryptococcal pathways that can induce a protective host response.
 Cryptococcus neoformans can undergo yeast-to-filament morphological transition. We and others have
shown that morphotype has a profound effect on cryptococcal interaction with various hosts. In mammalian
models of cryptococcosis, the yeast form is pathogenic while the filamentous form is attenuated/abolished in
virulence. Previously, we identified a key regulator of filamentation, Znf2. Deletion of ZNF2 locks cells in the
yeast form and enhances virulence. Overexpression of ZNF2 promotes filamentation in vitro and in vivo,
abolishes virulence, and can offer rare sterilizing immunity against an otherwise lethal challenge. Based on
these studies, we hypothesize that activating the cryptococcal filamentation program can elicit protective host
responses and alleviate cryptococcosis. The goal of this application is to characterize filamentation
pathways and identify those that induce protective host responses and attenuate cryptococcal
virulence.
 Capitalizing on our recent discoveries of self-filamentation in natural isolates of C. neoformans species
complex (serotype A and D), we performed multiple large genetic screens and identified candidate genes that
play important roles in filamentation in vitro. Among these candidates, multiple components of the osmotic
sensing pathway suppress filamentation in the serotype A reference strain H99 by inhibiting nuclear
translocation of the transcription factor Crz1, which acts upstream of Znf2. In Aim 1, we will define the
mechanism by which Crz1 distinguishes different stimuli to activate filamentation. In Aim 2, we will
characterize the identified candidates and establish their genetic relationship with Znf2 in controlling
cryptococcal virulence and morphology in vivo. In Aim 3, we will test the avirulent strains for their immunization
effect and their combined effect with Znf2 on host immunity. The work will generate a set of Cryptococcus
morphological mutants that induce protective host responses. These findings will reveal targets that can be
exploited in the future by us and others to investigate new measures against this deadly fungal disease.

## Key facts

- **NIH application ID:** 10403545
- **Project number:** 5R01AI140719-05
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Xiaorong Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $471,846
- **Award type:** 5
- **Project period:** 2018-06-11 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10403545

## Citation

> US National Institutes of Health, RePORTER application 10403545, Defining the genetic network governing cryptococcal morphological transition (5R01AI140719-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10403545. Licensed CC0.

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