# Fungal spore sensing by MDA5 is necessary for antifungal immunity against Aspergillus fumigatus

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2022 · $528,337

## Abstract

This R01 application explores the novel role the cytosolic RNA-sensing pattern-recognition receptor MDA5 plays
in mediating host resistance against the human fungal pathogen Aspergillus fumigatus. Our understanding of
how the immune system keeps fungal infections at bay in immune competent individuals remains ill-defined.
Currently, there is a critical gap in understanding the early interactions between fungal conidia and
tissue-resident phagocytes that are necessary for fungal clearance and host resistance. Our data
demonstrate a novel role of fungal conidia in triggering the cytosolic RNA-sensing MDA5 receptor and initiating
an IL28/IFNλ and CXCL10-CXCR3 inflammatory cascade which is necessary for host resistance in response to
Aspergillus fumigatus across a wide array of fungal isolates. Thus, our central hypothesis is that host
resistance pathways targeting A. fumigatus conidia serve as central hubs of inflammation providing
protective immunity against the broadest range of A. fumigatus isolates. In SA1 we examine how fungal
conidia growth dynamics and resistance to phagocyte-mediated killing enables triggering of the MDA5/MAVS
receptor. Importantly, we also examine the molecular mechanism(s) of how A. fumigatus conidia trigger this
cytosolic pattern-recognition receptor pathway. In SA2 we identify the specific leukocyte subsets which require
MAVS for IL28/IFNλ expression and host resistance following A. fumigatus challenge. This will be done using
novel Mavs conditional knock-out mouse lines, specifically examining the role of MDA5/MAVS signaling in the
cellular cross-talk between CCR2+ monocyte and neutrophil, which has been shown to be critical for maintaining
host resistance against A. fumigatus. Finally, in SA3 we elucidate the role of the CXCL10-CXCR3 inflammatory
axis in mediating neutrophil-dependent host resistance against A. fumigatus. Overall, this research fills a critical
knowledge gap regarding the mechanisms of protective mucosal immunity against A. fumigatus conidia through
the activation of a novel MDA5/MAVS and CXCL10-CXCR3 inflammatory cascade. These data, together with
other published fungal immune-mediated resistance pathways, could be used to risk stratify patients based on
their potential susceptibility to developing invasive aspergillosis. This personalized medicine approach could be
used to predict patients that should undergo early, aggressive monitoring and treatment for fungal infections in
order to drive better clinical outcomes for patients.

## Key facts

- **NIH application ID:** 10447696
- **Project number:** 5R01AI139133-04
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** JOSHUA J OBAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $528,337
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-11-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447696

## Citation

> US National Institutes of Health, RePORTER application 10447696, Fungal spore sensing by MDA5 is necessary for antifungal immunity against Aspergillus fumigatus (5R01AI139133-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10447696. Licensed CC0.

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