# Bidirectional paracrine signaling in the establishment of invasive aspergillosis

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $496,373

## Abstract

ABSTRACT
Invasive aspergillosis (IA) caused by Aspergillus fumigatus is characterized by uncontrolled filamentous hyphal
growth deep into host tissues and is a fatal disease of immunocompromised patients with mortality rates as high
as 90%. This high mortality rate indicates the critical need for improved antifungal therapeutic strategies. We
have uncovered a bidirectional lipid signaling system between the fungus and host that mediates invasive hyphal
growth and phagocyte activation. Based on strong preliminary data, this communication system consists of
structurally similar fungal and host ligands (e.g. oxylipins) that are recognized by specific fungal and host G
protein coupled receptors (GPCRs). The fungal and host oxylipins work in opposition to regulate fungal growth
and leukocyte functionality. We hypothesize that fungal and host oxylipins are cross-Kingdom molecular analogs
that signal through specific GPCR cascades, inducing penetrating hyphal growth and manipulating host defense
responses to drive IA progression. Our data not only provide new insight into how eukaryotic pathogens and
their hosts communicate with one another directly during disease but also provide a new foundation for
experimental approaches to decipher, manipulate, and control this communication system in favor of the host.
Accordingly, we will (1) Identify the oxylipins and their transcriptional cascades that regulate invasive
branching growth and (2) Characterize the receptors by which fungus and host recognize each other’s
oxylipins and the consequences of this recognition. GPCR are particularly propitious targets for therapeutic
design (40% of current pharmaceuticals target GPCR). Thus, upon completion of this work, we anticipate that
we will have delineated a new fungal-host ligand-receptor communication language amenable to therapeutic
intervention to inhibit filamentous invasive growth during human disease.

## Key facts

- **NIH application ID:** 10119974
- **Project number:** 1R01AI150669-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** NANCY P KELLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $496,373
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119974

## Citation

> US National Institutes of Health, RePORTER application 10119974, Bidirectional paracrine signaling in the establishment of invasive aspergillosis (1R01AI150669-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10119974. Licensed CC0.

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