# GM-CSF-Induced Metal Sequestration and Histoplasma

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2021 · $531,019

## Abstract

The pathogenic fungus, Histoplasma capsulatum, is endemic to the Midwestern and Southeastern US and 
is the most frequent cause of respiratory fungal infection. The organism thrives within the 
intracellular environ- ment of monocytes (Mo) and macrophages (Mɸ) and has the capacity to 
establish a latent state. Employing a multidisciplinary approach including metallomics, immunology, 
cell biology and bioinformatics, our studies have identified novel functions of granulocyte 
macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 that help to explain their 
disparate effects on the growth of the fungus with Mo/Mɸ. GM-CSF deprives the organism of zinc 
intracellularly while concurrently boosting production of reactive oxygen species. The end result 
is killing of yeast cells.  On the other hand, IL-4 promotes intracellular survival by fortifying 
the amount of zinc available to Histoplasma. Crucial to the activities of GM-CSF and IL-4 are 
metallothioneins (MTs), which store and donate zinc, and zinc transporters. They are a central node 
mediating the link between cytokine activation and effector function. For GM-CSF, MTs1 & 2 are 
essential whereas for IL-4, it is MT3. In this proposal, we will build on our work conducted during 
the last funding cycle and explore in depth how the MT- zinc axis regulates the activity of GM-CSF 
and IL-4 on human and mouse Mo/Mɸ. We have collected exciting data that glycolysis governs the 
expression of MTs1&2 in infected GM-CSF-stimulated Mo/Mɸ. On the other hand, MT3 tempers the 
glycolytic response in IL-4 activated in these cells. Aim 1 will decipher how glycolysis molds 
MT1&2 expression and intracellular Zn2+  distribution to bolster Mo/Mɸ effector function.  Aim 2 
will define the intracellular alterations in GM-CSF-activated Mo/Mɸ that deny the fungus access to 
zinc and the in vivo effect of MTs1&2 on host defenses exerted by these phagocytes. Aim 3 will 
elucidate the intersection of glycolysis and MT3 in shaping the physiology of IL-4 on 
Histoplasma-infected Mo/Mɸ. These studies will provide new insights into cytokine regulation of 
metabolism and metallobiology in Histoplasma-infected Mo/Mɸ.

## Key facts

- **NIH application ID:** 10189487
- **Project number:** 5R01AI106269-09
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** GEORGE S. DEEPE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $531,019
- **Award type:** 5
- **Project period:** 2013-05-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189487

## Citation

> US National Institutes of Health, RePORTER application 10189487, GM-CSF-Induced Metal Sequestration and Histoplasma (5R01AI106269-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10189487. Licensed CC0.

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