# Investigation of key proteases in the parasitic phase of Coccidioides

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $201,875

## Abstract

Project Summary
Coccidioides spp. are major fungal pathogens endemic to the Southwest United States, Central America, and
South America. In recent years, the incidence of coccidioidomycosis has continued to rise. Coccidioides infects
and kills immunocompetent individuals when they inhale spores from the soil and, despite current antifungal
treatment, continues to cause unacceptably high morbidity and mortality. The ability of Coccidioides to cause
disease depends on an elaborate developmental transition from mycelia found in the soil to the host form known
as a spherule, a morphology unique to Coccidioides. While this developmental process can be recapitulated in
the lab, the molecular determinants of spherulation remain poorly understood. Delineating which genes are
required for spherulation will lead to identification of therapeutic targets and accelerate discovery of new
antifungals for the treatment of coccidioidomycosis. We will focus this project on two families of secreted
proteases, subtilases and deuterolysins, and assess the role they play in spherulation. These protease families
have undergone evolutionary expansion in the Coccidioides lineage and, since spherules are unique to
Coccidioides, we hypothesize that their evolutionary expansion implicates them in the process of spherule
development. Protease inhibitors have proven to be successful therapeutics for other infectious diseases,
including HIV. The Coccidioides proteases that we discover to be required for the process of spherulation will be
excellent candidates for therapeutic targets.
 We will use a multipronged approach, including transcriptional profiling, protease inhibitor studies, and
genetics, to elucidate the role of key proteases in spherulation. This will leverage PI Sil’s extensive experience
with transcriptional profiling of dimorphic fungi, including Coccidioides, and collaborator Dr. Craik’s expertise on
the biology of proteases, including previous work on secreted proteases in pathogenic fungi. In Aim 1, we will
identify candidate secreted proteases involved in spherulation by profiling the transcriptome of multiple
developmental stages of Coccidioides to identify proteases whose expression is spherule-enriched. Additionally,
we will determine the effect of class-wide protease inhibitors on spherule formation, thereby implicating individual
protease families as key players in Coccidioides spherule development. In Aim 2, we will generate six mutant
Coccidioides strains, each lacking a secreted protease which is already implicated in spherulation from our
preliminary studies. Additionally, we will generate six more protease mutants based on prioritization from studies
in Aim 1. Using these deletion mutants, we will test whether each protease is required for spherulation. Our work
will provide a rich transcriptional profiling dataset as well as multiple deletion mutants that are critical for
dissecting the role of these two expanded protease families in the parasitic...

## Key facts

- **NIH application ID:** 10633259
- **Project number:** 5R21AI172185-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Anita Sil
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $201,875
- **Award type:** 5
- **Project period:** 2022-06-02 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10633259

## Citation

> US National Institutes of Health, RePORTER application 10633259, Investigation of key proteases in the parasitic phase of Coccidioides (5R21AI172185-02). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10633259. Licensed CC0.

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