# GDF-15 as a mediator of immune-regulated sickness response during infection

> **NIH NIH R21** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $188,767

## Abstract

Abstract:
The cytokine IFN-γ controls both protective and pathogenic host responses during
Toxoplasma gondii infection. By activating hemopoietic and non-hemopoietic cell
autonomous resistance mechanisms, this cytokine mediates toxoplasmastatic and
toxoplasmacidal activities that control pathogen replication. Much less is known about
how the same cytokine regulates host sickness responses. We have recently obtained
data indicating that IFN-γ regulates the systemic levels of the stress hormone GDF-15,
without affecting tissue levels of the hormone. GDF-15 is produced by a variety of immune
and tissue cell types in response to a broad range of stressors and acts through the
GFRAL-receptor expressed in the hindbrain to suppress appetite and induce weight loss.
Circulating GDF15 levels are elevated in a wide range of human diseases states including
infections and cancer and is often associated with poor clinical outcomes. GDF-15 has
been reported to have immunomodulatory effects on macrophages and lymphocytes.
Consistent with its systemic regulation by IFN-γ, IL-10 deficient animals infected with T.
gondii exhibit higher levels of circulating GDF-15. Thus we hypothesize that GDF-15 may
be a principal mediator of the pathogenic effects of IFN-γ that promote sickness
responses during T. gondii infection. Our experimental aims utilize a combination of
genetic and immunological approaches to rigorously evaluate our hypothesis that GDF-
15 mediates the effects of IFN-γ to promote sickness responses during Toxoplasma
infection. Our discovery that an immune cytokine controls of the systemic availability of
the stress hormone GDF-15 is an novel finding and may have implications for the
management of disease conditions associated with “cytokine storms”. Specific Aim 1 will
interrogate the role of specific proinflammatory cytokines in inducing elevations in tissue
GDF-15 levels during infection. Specific Aim 2 will test the hypothesis that IFNγ triggers
the release of GDF-15 from tissue stores by promoting its maturation and release,
putatively through a TRANS-cellular mechanism. Specific Aim 3 will interrogate the role
and function of endogenous GDF-15 in regulating the immune and sickness responses
in wildtype and IL-10-deficient mice during T. gondii infection. Completion of this project
will provide fundamental insights into how immune cytokines control the host sickness
response during infection. These insights may provide avenues to promote health by
decreasing disease sequelae that result from hyperactivation of immune response.

## Key facts

- **NIH application ID:** 10735886
- **Project number:** 5R21AI171670-02
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** George S. Yap
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $188,767
- **Award type:** 5
- **Project period:** 2022-11-07 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10735886

## Citation

> US National Institutes of Health, RePORTER application 10735886, GDF-15 as a mediator of immune-regulated sickness response during infection (5R21AI171670-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10735886. Licensed CC0.

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