# Molecular Basis of Human Toxoplasmosis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $668,225

## Abstract

PROJECT SUMMARY/ABSTRACT
Toxoplasma gondii is a common parasite of animals and frequent cause of accidental infection in humans.
Acute infections are generally controlled by the immune response, but persistent chronic infection ensues due
to survival of semi-dormant stages called bradyzoites that reside within tissue cysts. In immunocompromised
patients, rupture of the tissue cysts releases bradyzoites that can convert back to rapidly replicating
tachyzoites, a process that goes unrestricted due to decreased T-cell immunity. The potential for reactivation
presents a continued risk to immunocompromised patients due to the fact that neither the immune system nor
antibiotics can eradicate chronic infections. As such, there is still a need to understand fundamental
mechanisms of pathogenicity in order to develop more effective interventions. One of the key mediators of
innate and adaptive immunity to T. gondii is the production of interferons that activate cells to control the
parasite through a variety of mechanisms including nutrient depletion, targeting the parasitophorous vacuole
for destruction, or growth inhibition. As one of the world's most successful parasites, it is not surprising that T.
gondii has developed active mechanisms to block these immune control pathways. Our studies seek to define
the molecular bases of how T. gondii blocks or subverts interferon signaling to overcome host defenses. In the
prior funding period, we identified a secretory parasite protein that traffics to the host nucleus where it binds to
the transcription factor STAT1 and recruits a chromatin modifying complex to block gene expression induced
by both type I (IFN-β) and type II (IFN-γ) interferons. Our prior studies demonstrate that the ability of the
parasite to block type II IFN is primarily important in the acute infection while its ability to subvert type I IFN is
key in the central nervous system during chronic infection. We have also recently identified a second secreted
effector that also traffics to the host cell nucleus and blocks the type I IFN pathway. The proposed studies will
explore the molecular mechanisms by which these effectors inhibit IFN signaling by bradyzoites and thus
assure survival of tissue cysts that are responsible for chronic infection.

## Key facts

- **NIH application ID:** 10119229
- **Project number:** 5R01AI118426-07
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** L. David Sibley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $668,225
- **Award type:** 5
- **Project period:** 2015-02-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119229

## Citation

> US National Institutes of Health, RePORTER application 10119229, Molecular Basis of Human Toxoplasmosis (5R01AI118426-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10119229. Licensed CC0.

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