# T-cell Dysfunction as the basis of Disseminated Coccidioidomycosis

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $197,809

## Abstract

PROJECT SUMMARY/ABSTRACT
 Disseminated coccidioidomycosis (DCM) is an uncommon but life-threatening consequence of infection by
the fungus Coccidioides. Why some people get DCM and others a mild pulmonary disease (“Valley Fever”), or
remain asymptomatic is unknown. There are no effective treatments for DCM, and patients who survive must
remain on antifungals for life. Thus, there is an urgent need for a better understanding of DCM and for better
treatments.
 Based on decades of work by human and mouse immunologists, we believe the host's immune responses to
Coccidioides are defective in DCM and center on a failure of interferon-gamma (IFN-ɣ) production by helper T
cells (an immunogenetic program called Type-1 immunity). The importance of Type-1 immunity in the immune
response to Coccidioides is further evidenced by a patient we have described with DCM, hypomorphic function
of the IL-12 receptor, and a severe defect in Th1 differentiation. We showed in this case that DCM could be cleared
after innovative treatment with IFN-ɣ and a clinically-available blocking antibody of IL-4 receptor.
 Together, our preliminary and published data support the central hypothesis that Th cell dysfunction
provokes the development of DCM in a significant fraction of patients. If proven out, screening for Th
dysfunction and treatment with IFN-γ and IL-4 receptor blockade could rescue these genetic perturbations and
offer a treatment for DCM. To study the immune response in DCM, we have assembled a team of immunologists,
geneticists, and infection experts from UCLA, and have partnered with the Valley Fever Institute (VFI), the
largest Coccidioides clinic in California, to provide samples from DCM and uncomplicated Valley Fever (UVF).
Our Aims include 1) Identify type-2 skewed individuals with DCM and their genetic underpinnings;
and 2) Discover transcriptional patterns and pathways of immune dysfunction in DCM.
 The overall impact of this work is to accelerate the search for highly effective treatments for this life-
threatening fungal infection. Our work will also establish a genetic basis for predicting susceptibility to DCM that
can be tested in future work. Additionally, we will demonstrate in vitro the ability of two FDA-approved drugs
to skew memory T cell responses against Coccidioides, representing the first steps towards a clinical trial and the
establishment of a new treatment for an otherwise incurable disease.

## Key facts

- **NIH application ID:** 10226751
- **Project number:** 1R21AI149654-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** MANISH J BUTTE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $197,809
- **Award type:** 1
- **Project period:** 2021-02-02 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226751

## Citation

> US National Institutes of Health, RePORTER application 10226751, T-cell Dysfunction as the basis of Disseminated Coccidioidomycosis (1R21AI149654-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10226751. Licensed CC0.

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