# Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis

> **NIH NIH R37** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $597,417

## Abstract

Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection associated with
immune deficiency, particularly in the T cell compartment. C. albicans is a commensal
fungus that is the dominant causative species of OPC, and its key virulence trait is the
ability to form invasive hyphae. This morphologic transition in the fungus triggers
‘danger’ responses in oral epithelial cells (OECs), which are the first cell types to
encounter this microbe. In 2009, we showed that an effective immune response to
mucosal candidiasis in mice requires signaling by the cytokine IL-17 (IL-17A). The
importance of IL-17 was confirmed in humans with IL-17R-deficiencies. Using mice as a
model organism, we showed that in naïve settings (i.e., innate responses), IL-17 is made
by two innate lymphocyte cell subsets: gd-T and ‘natural’ Th17 cells (nTh17). In recall
(i.e., adaptive) responses, IL-17 is additionally made by conventional CD4+Th17 cells,
which augment the innate response to accelerate fungal clearance. Collectively, IL-17+
cells comprise “Type 17” immunity. Regardless of source, IL-17 signals through a
heterodimer of IL-17RA and IL-17RC, which is highly expressed on cells of the stromal
and epithelial compartments. The initiating event in OPC is exposure of OECs to C.
albicans. However, it remains unclear how early epithelial recognition events lead to
activation of Type 17 responses, and why these responses occur only in response to
hyphae. In a landmark discovery the co-I (Dr. Naglik) showed that the danger response
in OECs is activated by a virulence factor, Candidalysin, the first pore-forming peptide
toxin identified in any human fungal pathogen. Candidalysin is secreted only by hyphae
and permeabilizes OEC membranes. Candidalysin triggers a MAPK-dependent
pathway, leading to upregulation of cytokines, chemokines and antimicrobial peptides
that are essential for immunity to OPC. Our overarching goal in this continuation is to
define in depth the mechanisms by which host-and pathogen-derived factors
coordinate effective Type 17 immunity against C. albicans.

## Key facts

- **NIH application ID:** 10551422
- **Project number:** 4R37DE022550-11
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Sarah L Gaffen
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $597,417
- **Award type:** 4N
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10551422

## Citation

> US National Institutes of Health, RePORTER application 10551422, Host and Fungal Regulation of Type 17 Immunity to Oral Candidiasis (4R37DE022550-11). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10551422. Licensed CC0.

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