# Interplay between the heat shock response and histidine kinase pathways in the thermally dimorphic fungal pathogen Histoplasma capsulatum

> **NIH NIH R01** · J. CRAIG VENTER INSTITUTE, INC. · 2022 · $487,500

## Abstract

Project Summary
 Histoplasma capsulatum is one of several systemic dimorphic fungal pathogens that switch their growth
program from an infectious mold form in the soil to a pathogenic yeast form in mammalian hosts. H. capsulatum
causes up to 25,000 life-threatening infections per year in the U.S. alone with up to 50% mortality rate, and is
the most common cause of fungal respiratory infections in healthy hosts. Infection occurs when the soil is
disrupted, facilitating dispersion of hyphal fragments or spores that are inhaled by humans. Spores and hyphal
fragments are the primary infectious agents; however, once introduced into the host, the pathogen converts to a
budding-yeast form, which survives and replicates within host macrophages. In the laboratory, the switch between
the infectious and parasitic states is modeled by changing the growth temperature: cells grow in the filamentous
form (hyphal) at room temperature, whereas growth at 37ºC is sufficient to trigger growth in the yeast form and
expression of virulence factors.
 Despite its importance to human health, very little is known about how H. capsulatum senses and responds
to human body temperature. Our prior research findings significantly contributed to the understanding of the
molecular mechanism used by H. capsulatum to regulate cell morphology and virulence gene expression: we found
that four transcriptional regulators, Ryp1,2,3,4, are the core components of a temperature-responsive intersecting
regulatory network. In unpublished studies, we comprehensively identified Ryp-interacting proteins with potential
regulatory roles. Among the diverse set of Ryp2-interacting proteins, we characterized a heat shock protein,
Hsp90, and two proteins, Ssk1 and Skn7, with predicted response regulator domains. We found that Hsp90,
Ssk1 and Skn7 regulate yeast phase growth in H. capsulatum. Hsp90 plays a key role in the heat shock
response; and response regulators work with sensor histidine kinases and are often involved in sensing
environmental signals. In this project, we propose to build upon our previous findings and fully characterize the
involvement of the heat shock response and histidine kinase pathways in regulating Ryp proteins, cell
morphology and virulence traits in H. capsulatum in response to host temperature. These studies will provide
fundamental information on how cells sense temperature and turn on the appropriate virulence pathways in the host.
Ultimately, the information obtained from this project can be used to develop therapeutics for H. capsulatum
infections and help prevent other dimorphic fungal infections.

## Key facts

- **NIH application ID:** 10215404
- **Project number:** 5R01AI137418-04
- **Recipient organization:** J. CRAIG VENTER INSTITUTE, INC.
- **Principal Investigator:** Sinem Beyhan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $487,500
- **Award type:** 5
- **Project period:** 2018-08-14 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215404

## Citation

> US National Institutes of Health, RePORTER application 10215404, Interplay between the heat shock response and histidine kinase pathways in the thermally dimorphic fungal pathogen Histoplasma capsulatum (5R01AI137418-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10215404. Licensed CC0.

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