# T-bet-regulated myeloid innate defense against Toxoplasma gondii

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $315,000

## Abstract

Abstract
Toxoplasma gondii is the causative agent of toxoplasmosis, and it is estimated to infect a third of the human
population globally. T. gondii infection can result in serious complications including congenital toxoplasmosis of
the fetus and death among immunocompromised individuals. Unfortunately, current regimens for T. gondii
treatment show high rates of toxicity, and are only able to treat the acute stage of the parasitic infection.
Therefore, there is an urgent need develop new medicines with specific efficacy against T. gondii. Host
immunity against T. gondii is defined by a MyD88-dependent IL-12 response, which generates a CD4+ Th1-
derived IFN-γ response necessary for host survival. The transcription factor T-bet is considered essential for
the development and function of innate lymphoid cells (ILCs) and TH1s during T. gondii infection. T-bet is
traditionally considered the master regulator of lymphocyte-derived interferon-gamma (IFN-γ) production. Yet,
T-bet-independent ILC- and TH1-derived IFN-γ is insufficient for host immunity, demonstrating that IFN-γ alone
is insufficient for host defense and that T-bet must be inducing an IFN-γ-independent anti-parasitic response.
For instance, despite robust IFN-γ production, T-bet-deficient mice succumb to infection significantly faster
than animals lacking lymphocytes, suggesting T-bet-expressing myeloid cells are required for host survival.
Our objective is to define T-bet’s role in regulating myeloid cell-dependent immunity against T. gondii. Our
preliminary findings have identified a unique T-bet expressing CD11c+MHCII- myeloid cell population that are
critical for eliminating T. gondii. Based on these results, we hypothesize that T-bet expression in myeloid cells
regulates pathogen clearance and host survival during T. gondii infection. To test our hypothesis, we will (i)
determine the underlying mechanism(s) of T-bet in regulating myeloid cell-mediated defense against T. gondii
(AIM 1) and (ii) define the molecular functions of T-bet-expressing myeloid cells in mediating host resistance
against T. gondii (AIM 2). We will utilize unbiased T-bet reporter mice and cell-type-specific T-bet-deficient
mice established in our lab, in combination with various molecular biology techniques, spectral cytometry,
immunofluorescence, and single-cell RNA-sequencing. Together, these experiments will for the first time
establish T-bet’s role in mediating myeloid cell-dependent host defense against T. gondii, thereby providing
novel specific targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10873064
- **Project number:** 5R01AI168056-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** AMERICO HARRY LOPEZ-YGLESIAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $315,000
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873064

## Citation

> US National Institutes of Health, RePORTER application 10873064, T-bet-regulated myeloid innate defense against Toxoplasma gondii (5R01AI168056-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873064. Licensed CC0.

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