# Antifungal immunity in Hirschsprung-Associated Enterocolitis

> **NIH NIH R21** · CEDARS-SINAI MEDICAL CENTER · 2020 · $255,000

## Abstract

PROJECT SUMMARY
Hirschsprung associated enterocolitis (HAEC) is the most frequent complication in children with Hirschsprung
disease (HSCR), resulting in frequent hospitalizations and half of deaths in this population. The mechanisms
underlying HAEC are poorly understood. We reported in a microbiome study that Candida spp. are specifically
enriched in stool of HAEC patients, and we report here that HAEC patients have elevated anti-Saccharomyces
cerevisiae antibody (ASCA) titers. Since ASCA levels are known to be associated with inflammatory bowel
disease (IBD), we hypothesized that other risk factors for IBD might be associated with HAEC. We genotyped
single nucleotide polymorphisms (SNPs) in a small cohort of HSCR patients and found preliminary evidence
that 37 SNPs previously found to associate with IBD may also be linked to the risk of developing HAEC. One of
these genes, CARD9, particularly caught our interest because CARD9 is involved in host immune responses to
intestinal microbes, especially fungi, as a signaling molecule involved in anti-fungal C-type lectin receptor
signaling. We have established a mouse model of HAEC (Ednrb-null mouse model) and found that creating
Ednrb-Clec7a double mutant mice (Clec7a gene encodes for the antifungal C-type lectin receptor Dectin-1)
causes a 5-fold increase in fecal C. albicans and 4-fold increased enterocolitis severity compared with controls.
We further observed in the Ednrb-null model that natural intestinal colonization with Candida utilis and
Rhodotorula mucilaginosa is associated with the risk of developing HAEC. Finally, HAEC severity was reduced
65% when animals were treated with the antifungal drug isavuconazole. Together, these discoveries suggest
new mechanisms for HAEC implicating intestinal fungi and antifungal immunity. Our overall hypothesis is that
HSCR patients with genetic susceptibility to developing HAEC respond inappropriately to changes in the
intestinal microbiota, (with a particular interest in fungi) leading to a difficult-to-treat colitis. This hypothesis will
be investigated in the following two aims: 1) investigate the role of antifungal immunity gene Card9 in a mouse
model of HAEC; 2) define the role of Candida utilis and Rhodotorula mucilaginosa in the same mouse model of
HAEC. The line of investigation outlined here may lead to greater rationale for treating HAEC patients using
personalized approaches and may lead to methods for early identification of patients at high risk of developing
HAEC.

## Key facts

- **NIH application ID:** 9883716
- **Project number:** 5R21AI142422-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Philip Kent Frykman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $255,000
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883716

## Citation

> US National Institutes of Health, RePORTER application 9883716, Antifungal immunity in Hirschsprung-Associated Enterocolitis (5R21AI142422-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9883716. Licensed CC0.

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