# HIF Regulation of Histoplasma Pathogenesis

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $401,250

## Abstract

Project Summary
 The dimorphic fungus, Histoplasma capsulatum (Hc), is endemic to the Midwestern and Southeastern US
and is the most frequent cause of fungal respiratory infection. Yeast cells thrive in the intracellular environment
of macrophages (M) until these phagocytes are activated by cytokines such as interferon- or granulocyte M
colony-stimulating factor. The transcriptional elements that license M to promote clearance of the fungus are
largely unknown. We have discovered that the transcription factors hypoxia inducing factors (HIF)-1 and -2
calibrate the behavior of M infected with Hc. In a recent publication, we reported that the lack of HIF-1 in M
exacerbates infection with Hc by promoting the generation of interleukin (IL)-10. The absence of both HIF-1
and -2 further exaggerates IL-10 production by M. Excessive IL-10 dampens the ability of activating cytokines
to arm the anti-Hc function of M. We demonstrate that Hc induces HIFs and that pharmacologically inflating HIF
accrual enhances the anti-Hc activity of mouse and human M. These data triggered two hypotheses: 1) HIFs
in M are required to temper IL-10 generation, and 2) pharmacologically amplifying expression of HIFs arms M
to exert anti-Hc activity. To test these hypotheses, we propose three Specific Aims. Aim 1 will examine the
interplay between HIFs and metabolism. Specifically, we will determine if a glycolytic metabolite initiates and
tumor necrosis factor- sustains expression of HIFs. We will determine if overproduction of a specific metabolite
by infected HIF-deficient cells promotes IL-10 release. Specific Aim 2 will examine how HIFs regulate IL-10. We
will determine if miRNA-27a is involved in the generation of IL-10 and if IL-10 modifies the metabolism of HIF-
deficient cells. We will test the possibility that a metabolic product regulates the expression of an miRNA that
controls the decay of IL-10 transcription. We will ascertain if IL-1receptor antagonist is a downstream effector of
IL-10-mediated inhibition of M function. Specific Aim 3 will investigate how pharmacological activation of HIFs
promotes the anti-Hc activity of MWe will identify a mechanism and the in vivo effect of these agents. We
expect these studies to provide a greater understanding of the regulation of M function in response to Hc.

## Key facts

- **NIH application ID:** 9851332
- **Project number:** 5R01AI133797-03
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** GEORGE S. DEEPE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $401,250
- **Award type:** 5
- **Project period:** 2018-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851332

## Citation

> US National Institutes of Health, RePORTER application 9851332, HIF Regulation of Histoplasma Pathogenesis (5R01AI133797-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851332. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*