# Intracellular Proliferation of the fungal pathogen Histoplasma capsulatum

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $389,949

## Abstract

PROJECT SUMMARY
Histoplasma capsulatum is a fungal pathogen that infects both immunocompromised and immunocompetent
individuals. The innate immune system alone is ineffective in controlling Histoplasma yeasts because
Histoplasma invades and thrives within host phagocytic cells. Histoplasma’s parasitism of macrophages
requires acquisition and metabolism of suitable nutritional resources from the host cell, yet the host molecules
that serve as nutrients for are largely unknown. Preliminary investigations have shown intracellular yeasts are
gluconeogenic and likely consume amino acids, particularly compounds that are related to glutamate. These
findings provide a critical foothold for identifying the host molecules consumed by Histoplasma yeasts.
This proposal takes a multidisciplinary approach, integrating evidence from molecular biology, genetics, and
metabolomics to determine the host molecules available to Histoplasma yeasts within the phagosome and how
they are metabolized to meet the carbon and energy needs within host cells. The intracellular growth
requirement for glutamate dehydrogenase activity narrows the potential host molecules for metabolic carbon to
glutamate-related amino acids or glutamate-generating host molecules. Transcriptional and metabolite
profiling will be combined with functional tests to define the metabolic pathways necessary for Histoplasma
proliferation within host macrophages. Isotopic labeling of host metabolites will be used to follow their import
and subsequent incorporation into Histoplasma metabolism intermediates over time to demonstrate the flux of
carbon from macrophage to intracellular yeasts and identify host substrate entry points into yeast central
carbon metabolism. These findings will be genetically tested by characterization of Histoplasma’s amino acid
and peptide transporters and RNAi-based interference with candidate host metabolite import into intracellular
Histoplasma yeast cells. Together these data will provide multiple lines of evidence to define how Histoplasma
yeasts exploit the phagosome as a replication-permissive intracellular niche during host infection.
This proposal is submitted in response to Funding Opportunity Announcement (FOA) PA-19-083 “Novel
approaches to understand, prevent, treat, and diagnose coccidioidomycosis (Valley Fever) and other select
endemic fungal infections.” The proposal answers the announcement’s goal to address the pathogenesis of
endemic fungi with the ultimate goal of advancing the field towards solutions for treatment of endemic
mycoses. Of the dimorphic endemic fungal pathogens, Histoplasma is the best molecularly characterized
fungus and it has the most advanced molecular genetics to facilitate functional testing for mechanistic studies.
The results of our studies will reveal new disease treatment avenues by highlighting transport and metabolic
reactions essential for the narrow metabolism imposed on Histoplasma by its residence within macrophage
phagosomes. Ou...

## Key facts

- **NIH application ID:** 9865163
- **Project number:** 1R01AI148561-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Chad A Rappleye
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $389,949
- **Award type:** 1
- **Project period:** 2020-03-10 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9865163

## Citation

> US National Institutes of Health, RePORTER application 9865163, Intracellular Proliferation of the fungal pathogen Histoplasma capsulatum (1R01AI148561-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9865163. Licensed CC0.

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