# Translation initiation factors driving persistence of Toxoplasma gondii bradyzoites in neurons

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $573,797

## Abstract

PROJECT SUMMARY
The protozoan parasite Toxoplasma gondii can cause recurring opportunistic infections due to its ability to persist
as a latent form (bradyzoite) within patients. There is no treatment that targets bradyzoite cysts, which reconvert
into the destructive proliferative stage (tachyzoites) in the immune compromised. Patients suffering from
reactivated toxoplasmosis frequently present with life-threatening neurological problems, underscoring the
significance of bradyzoite cysts in the brain. A better understanding of the mechanisms that drive the
development of bradyzoites in neurons is necessary to devise new therapies that prevent their formation and
persistence. To address this need, we developed a novel model of spontaneous tissue cyst formation in neurons
using Lund human mesencephalic (LUHMES) cells. We will use this innovative system to determine the
mechanisms underlying the changes in protein synthesis that are required for bradyzoite formation. Based on
our previous collaborative work, we hypothesize that translation initiation factors coordinate changes in
5’-leader sequences of key mRNAs, resulting in changes in protein synthesis that induce conversion to
bradyzoites. Translation begins with the binding of an eIF4F complex to the 5’-cap, which then recruits eIF2,
which carries Met-tRNA. We previously showed TgIF2 is phosphorylated during bradyzoite conversion, which
lowers its abundance and can alter start codon selection. Aim 1 will determine how TgIF2 becomes
phosphorylated and which mRNAs are preferentially translated during spontaneous bradyzoite conversion in
neurons. Our RiboSeq approach will reveal areas within 5’-leaders that regulate translation, such as upstream
open reading frames (uORFs) or secondary structures, the latter of which will be identified by generating the first
RNA “structurome” for Toxoplasma in Aim 2. As these structures are resolved by helicase activity of eIF4F, Aim
2 will also delineate the functions of the multiple TgIF4F complexes we have uncovered in the parasites.
Together, these studies will determine how cellular signals coordinate translation initiation factors to reprogram
the translatome to trigger the spontaneous formation of bradyzoites in human neurons. Completion of this study
will have a sustained high impact on the field by providing significant new insights into the complex mechanisms
that Toxoplasma uses to persists in its host, which will reveal novel points for therapeutic intervention.

## Key facts

- **NIH application ID:** 10751024
- **Project number:** 5R01AI172752-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** William J Sullivan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $573,797
- **Award type:** 5
- **Project period:** 2022-12-08 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10751024

## Citation

> US National Institutes of Health, RePORTER application 10751024, Translation initiation factors driving persistence of Toxoplasma gondii bradyzoites in neurons (5R01AI172752-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10751024. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*