# Gene circuits that control morphology in Histoplasma

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $479,102

## Abstract

Project Summary
 Histoplasma capsulatum (Hc) is a thermally dimorphic fungus that is thought to be the most common
cause of fungal respiratory infections in healthy humans. Hc grows in a multicellular hyphal form in the
environment. Once inhaled by mammals, Hc converts to a unicellular yeast form that colonizes macrophages.
Temperature is a key signal that is sufficient to trigger the switch from the soil to host form (and vice versa); in
the laboratory, room temperature promotes hyphal (mold-form) growth whereas 37ºC promotes yeast-phase
growth. The long-term goal of this research is to determine the molecular basis of how temperature regulates
morphology and virulence in thermally dimorphic fungi. By elucidating how Hc cells sense and respond to host
temperature, we will define critical molecular landmarks that promote changes in morphology as well as the
expression of virulence traits. In previous work, we identified four transcription factors, Ryp1, 2, 3, and 4, that
promote yeast-form growth in response to host temperature. The Ryp proteins are absolutely required for yeast-
phase morphology as well for the vast majority of the temperature-dependent gene expression program. Over
the last funding period, we uncovered evidence that Ryp1 and Ryp2 are regulated post-transcriptionally.
Additionally, to identify regulatory mechanisms that antagonize the Ryp pathway at low temperature, we isolated
yeast-locked mutants that inappropriately activate the Ryp pathway in the absence of the normal high
temperature signal. We determined that the cell surface signaling mucin Msb2 is required for (1) inhibition of Ryp
accumulation and (2) establishment of hyphal growth in response to low temperature. Additionally, transcriptional
profiling of the msb2 mutant allowed us to identify compact gene regulons that are associated with either hyphal
formation or yeast-phase growth, including the identification of putative virulence factors whose expression is
associated with growth in the yeast form independent of temperature. Here we will (1) investigate how
temperature regulates the Histoplasma pathogenic program by elucidating the molecular mechanisms that
regulate the Ryp pathway; (2) elucidate how the Ryp and Msb2 pathways, which oppose each other, are able to
sense temperature; and (3) utilize our temperature-defined regulatory circuits for virulence gene discovery.
These experiments will result in a detailed molecular understanding of how temperature triggers critical cell fate
changes that are linked to the ability of Hc to cause disease.

## Key facts

- **NIH application ID:** 10073079
- **Project number:** 2R37AI066224-16
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Anita Sil
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $479,102
- **Award type:** 2
- **Project period:** 2005-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073079

## Citation

> US National Institutes of Health, RePORTER application 10073079, Gene circuits that control morphology in Histoplasma (2R37AI066224-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073079. Licensed CC0.

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