# Immunopathogenesis of Histoplasmosis and TNF

> **NIH NIH R21** · UNIVERSITY OF CINCINNATI · 2022 · $209,982

## Abstract

Project Description
The pathogenic fungus, Histoplasma capsulatum, is endemic to the Midwestern and Southeastern US and is
the most frequent cause of respiratory fungal infection. Activation of T cell-mediated immunity is considered to
be a major mechanism for host control of infection. Although most infections are mild, in immunosuppressed
individuals it may become life-threatening. The tumor necrosis factor (TNF)- antagonists are one of the more
common immunosuppressive drugs that undermine immunity and predispose to progressive histoplasmosis.
These agents have improved the lives of many with inflammatory diseases yet put them at risk for disseminat-
ed histoplasmosis. As in humans, neutralization of TNF- in mice disables immunity to the fungus. In infected
mice given anti-TNF-we discovered that conventional lung Foxp3-CD4+ T cells inhibited the ability of IFN--
stimulated M to kill yeast cells. Within this population, we identified the presence of a Foxp3-CD4+CD25- T cell
subset that bears multiple inhibitory receptors including but not limited to PD-1, Tim-3, and TIGIT. We postulate
this T cell subpopulation disarms the growth inhibitory properties of activated macrophages and dendritic cells.
In the first aim we will 1) determine if this subset directly impairs the ability of M stimulated with IFN- or GM-
CSF or dendritic cells to eliminate the fungus; 2) determine if signaling through TNF receptor 1 or 2 is key for
the emergence of this population, and 3) ascertain if these cells negatively regulate immunity in vivo. In the
second aim, we will examine the transcriptome of these cells to identify regulatory elements that prompt the
increased expression of inhibitory receptors. In parallel, we will examine the metabolic properties of these cells
to determine if changes in metabolism may account for the upregulation in inhibitory receptors. We will unite
metabolism with RNA-seq to identify interconnecting networks between metabolism and transcriptomics These
studies will provide new insights into the biology of T cells in the context of TNF- antagonism.

## Key facts

- **NIH application ID:** 10377422
- **Project number:** 5R21AI160722-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** GEORGE S. DEEPE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $209,982
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10377422

## Citation

> US National Institutes of Health, RePORTER application 10377422, Immunopathogenesis of Histoplasmosis and TNF (5R21AI160722-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10377422. Licensed CC0.

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