# FUNGAL PATHOGENESIS OF MODERATE TO SEVERE ASTHMA

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $505,156

## Abstract

The broad, long-term objective of this proposal is to understand the causes of chronic asthma and thereby
improve diagnosis and therapy of this common and debilitating ailment. We showed previously how innate
immune activation in response to fungal infection of the airway is linked to the development of T helper 2 (TH2)-
biased allergic airway inflammation and associated diseases (asthma and chronic rhinosinusitis). Fungi are
ubiquitous in human environments and readily gain access to the airway mucosal membrane through constant
inhalation of conidia (spores). We have shown that fungi isolated from the human airway can cause airway
hyperreactivity in mice, suggesting that airway fungal growth, i.e., airway mycosis, activates innate and
acquired immune responses that could cause asthma in susceptible individuals. This is further supported by
our discovery in mice that secreted fungal proteinases cleave fibrinogen in the airways to form cleavage
products (FCPs) that activate Toll like receptor 4 (TLR4) to induce fungistatic innate immune responses.
However, how these factors mediate allergic inflammation in the lungs remain unknown. Our central
hypothesis states that fungal proteinase-mediated cleavage of fibrinogen initiates allergic airway disease and
fungistatic innate immune responses in the airways. We will test this hypothesis through the following Aims: 1)
Determine the molecular mechanism by which FCPs initiate allergic inflammation and antifungal immunity
through TLR4. Hypotheses: Fungal proteinases cleave fibrinogen to yield FCPs that 1) signal through TLR4 via
the CD18-CD11b integrin heterodimer (Mac-1) to 2) activate STAT6 and NF-κB. We will use mice with
constitutive and targeted deletions of STAT6, NF-κB, and Mac-1 as well as mice harboring a mutation in the
fibrinogen gamma chain that prevents binding to Mac-1 to test our hypothesis, confirming our findings using
human monocyte derived macrophages. 2) Determine how FCPs initiate allergic inflammation and antifungal
immunity through airway epithelia of asthmatics. Hypotheses: 1) Epithelial cells secrete coagulant factors in
response to fungal proteinases 2) FCPs initiate allergic and anti-fungal responses mediated by enhanced
secretion of airway coagulant factors by airway epithelial cells. We will determine the physiological significance
of FCP-mediated induction of clotting factors (e.g., fibrinogen, prothrombin) regarding antifungal immunity and
chronic allergic inflammation using animal models of asthma and human airway epithelial cells. 3) Determine
the mechanism of innate antifungal immune dysfunction in asthmatics with airway mycosis. Hypothesis:
Immune cells from a subset of patients with moderate to severe asthma and airway mycosis are unable to
restrain fungal growth in vitro. We will examine the fungistatic ability of human monocyte-derived macrophages
(HMDM) against fungal conidia. To resolve the signatures of effective and ineffective innate immune
responses to fungi in a...

## Key facts

- **NIH application ID:** 9876979
- **Project number:** 5R01AI135803-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** DAVID B CORRY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $505,156
- **Award type:** 5
- **Project period:** 2018-03-23 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876979

## Citation

> US National Institutes of Health, RePORTER application 9876979, FUNGAL PATHOGENESIS OF MODERATE TO SEVERE ASTHMA (5R01AI135803-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9876979. Licensed CC0.

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