# Immunopathogenesis in fungal asthma

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2024 · $459,000

## Abstract

The objective of this competitive renewal R01 is to continue to uncover mechanisms that contribute to the severity
of disease in the 30%+ of asthmatics who are sensitized to fungi. Leukotrienes, immunopathogenic mediators
derived from the metabolism of arachidonic acid (AA) by 5-lipoxygenase (5-LOX), are often elevated in severe
asthma. As such, this pathway is a therapeutic target of the FDA-approved anti-asthmatic drugs Zileuton®/Zyflo®
(inhibits 5-LOX) and Singulair®/Montelukast® (leukotriene receptor antagonist). A second enzyme involved in
AA metabolism is 12/15-lipoxygenase (12/15-LOX). We show that asthmatic C57BL/6 wild-type mice have
increased lung expression of Alox15 mRNA as well as increased levels of the 12/15-LOX product 12-HETE
compared to naïve or vehicle treated mice. Asthmatic 12/15-LOX deficient mice (Alox15-/-) demonstrated lower
airway hyperactivity (AHR) in the presence of lower type 1 and type 2-associated mediators, lower chemokine
levels and decreases in multiple myeloid cell types. Bone marrow chimera studies identified 12/15-LOX
expression in hematopoietic cells as contributing to exacerbation of allergic fungal asthma. Intriguingly, the
absence of 12/15-LOX expression in dendritic cells and/or macrophages (via Cd11c Cre/Alox15 floxed mice)
had no effect on AHR, implicating other hematopoietic cells in driving 12/15-LOX mediated AHR during allergic
fungal asthma. In other data, we demonstrate the development of a 12/15-LOX reporter mouse in which 12/15-
LOX is HA-tagged and show feasibility of using these mice to identify 12/15-LOX expressing cells in the lung by
flow cytometry. Thus, 12/15-LOXHA mice will serve as a novel tool to identify hematopoietic/myeloid cell type(s)
expressing 12/15-LOX during allergic fungal asthma. In other studies, we found that mice deficient in immune
response gene 1 (Irg1-/-) (also known as aconitate decarboxylase, Acod1), which generates the
immunomodulatory TCA cycle metabolite itaconate, clear A. fumigatus from the lung more efficiently, seemingly
as a result of increased proinflammatory responses and augmented macrophage and neutrophil antifungal
activity. In contrast, Irg1/Acod1-/- subjected to allergic fungal asthma had increased AHR, indicating a protective
role for itaconate. Collectively, we hypothesize that the severity of allergic fungal asthma is dictated by the
balance between specific lipidomic (i.e. 12/15-LOX) and metabolomic (itaconate) responses. The specific aims
of the proposal are: (1) to define hematopoietic-associated 12/15-lipoxygenase dependent mechanisms
promoting AHR during allergic fungal asthma, (2) to define mechanisms of itaconate-mediated regulation of AHR
during allergic fungal asthma and (3) to define the therapeutic potential of 12/15-LOX and itaconate on AHR
during allergic fungal asthma.

## Key facts

- **NIH application ID:** 10888864
- **Project number:** 2R01HL122426-10
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Chad Steele
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,000
- **Award type:** 2
- **Project period:** 2014-12-08 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888864

## Citation

> US National Institutes of Health, RePORTER application 10888864, Immunopathogenesis in fungal asthma (2R01HL122426-10). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10888864. Licensed CC0.

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