# GCN5a and cyst development in the AIDS-opportunistic pathogen Toxoplasma

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $190,135

## Abstract

PROJECT SUMMARY
Toxoplasma gondii is an intracellular protozoan parasite that poses a major threat to patients
with HIV/AIDS. The replicative stage (tachyzoite) develops into a latent stage (bradyzoite) that
resides inside host cells as cysts in brain, heart, and skeletal muscle tissues. Tissue cysts
remain in the host for life, as they are impervious to the immune response and currently
approved drugs, and give rise to recurrent reactivation of infection in immune compromised
patients. Despite its clinical importance, little is known about the regulation of gene expression
required for the tachyzoite to bradyzoite transition. Our lab has previously established that
epigenetic modifications, namely the acetylation of histone proteins by GCN5 family lysine
acetyltransferases (KATs), regulate gene expression changes required for bradyzoite
differentiation. Toxoplasma possesses two GCN5 KATs, GCN5a and GCN5b. Previously, we
have shown that GCN5b partners with a complex of proteins to regulate the expression of
housekeeping genes and is essential for the viability of tachyzoites; in contrast, GCN5a is
dispensable in tachyzoites but is required to upregulate genes associated with stress responses
that induce bradyzoite development. Importantly, loss of GCN5a results in a failure to activate
bradyzoite-specific genes BAG1 and LDH2 in bradyzoite culture conditions. Consequently, we
hypothesize that GCN5a works in a multi-subunit complex that is critical for tachyzoite
development into bradyzoites. The aforementioned studies were completed in type I RH
parasites, and while this strain does not develop into mature bradyzoites at high frequency, it
has served to support the idea that GCN5a activates genes in response to bradyzoite inducing
agents. It is now imperative that we examine the function of GCN5a in type II parasites, which
readily form mature tissue cysts in vitro and in vivo. In this R21 application, we propose to
address our hypothesis with two specific aims: (i) We will determine the role of GCN5a in
bradyzoite conversion by characterizing mutants made in cystogenic parasites. (ii) We will
identify proteins that comprise the GCN5a KAT complex in both tachyzoite and bradyzoite
growth conditions, which promises to reveal new players involved in tissue cyst formation. The
study of GCN5a provides a unique opportunity to gain much-needed knowledge about the
formation of latent tissue cysts. Completion of our specific aims will generate reagents and
datasets that are required to understand the role of GCN5a in bradyzoite development and
generate further hypotheses that will determine how Toxoplasma persists in HIV/AIDS patients.

## Key facts

- **NIH application ID:** 10003563
- **Project number:** 1R21AI152583-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** William J Sullivan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $190,135
- **Award type:** 1
- **Project period:** 2020-01-21 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003563

## Citation

> US National Institutes of Health, RePORTER application 10003563, GCN5a and cyst development in the AIDS-opportunistic pathogen Toxoplasma (1R21AI152583-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10003563. Licensed CC0.

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