# Interferon-mediated control mechanisms in human cells

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2021 · $196,875

## Abstract

Abstract
Toxoplasma gondii is a widespread parasite of animals that causes zoonotic infection in humans. Although
acute infections in healthy adults are normally resolved without serious consequences, infection of
immunocompromised individuals can lead to serious complications. Toxoplasma gondii is an obligate
intracellular parasite, capable of infecting all nucleated cells in the body, including monocytes and
macrophages. Control of infection relies on production of IFN-γ, which is essential to upregulate antimicrobial
pathways in both hematopoietic and non-hematopoietic cells. Interferons activate STAT transcription factors to
upregulate interferon stimulated genes (ISGs), many of which participate in antimicrobial defenses. Compared
to studies in the murine system, our knowledge of how these pathways control T. gondii replication in human
cells is relatively limited. Treatment of human cells with type I (IFN-β) or type II (IFN-γ) interferon leads to
control of T. gondii replication. A variety of different control pathways have been implicated including nutrient
limitation, guanylate binding proteins, autophagy, and production of reactive oxygen or nitrogen species.
However prior studies have only focused on a few of the components that operate in each pathway, limiting our
knowledge of their relative importance. To provide a comprehensive analysis of ISGs that are required for IFN-
mediated control of T. gondii, we have developed a FACS-based screen to monitor parasite replication in
different human cell types. Genome wide CRISPR/Cas9 screens will be employed to identify genes whose loss
results in an inability to control T. gondii replication in IFN-treated cells. In parallel, we will use a lentiviral over-
expression strategy to screen libraries of type I and type II ISGs to identify effectors that induce control of
parasite replication. Collectively these approaches should define the repertoire of human genes that are
necessary and sufficient to control intracellular parasites. Understanding such mechanisms may be important
in overcoming the resistance to clearance seen in chronic toxoplasmosis and may also be important in control
of other intracellular pathogens.

## Key facts

- **NIH application ID:** 10194376
- **Project number:** 5R21AI154048-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** L. David Sibley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $196,875
- **Award type:** 5
- **Project period:** 2020-06-16 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194376

## Citation

> US National Institutes of Health, RePORTER application 10194376, Interferon-mediated control mechanisms in human cells (5R21AI154048-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10194376. Licensed CC0.

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