# ER stress and calcium in host adaptation of A. fumigatus

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $415,286

## Abstract

Infections with the mold pathogen Aspergillus fumigatus continue to be a major obstacle to the effective
management of immunocompromised patients, particularly those with hematologic malignancies, organ
transplants, chronic granulomatous disease, or cystic fibrosis. Despite several advances in our understanding
of this infection, it is unclear how this fungus adapts so readily to the host environment, and escapes clearance
in situations of chronic colonization. The unfolded protein response (UPR) is a signaling pathway that senses
the stress load on the endoplasmic reticulum (ER) and communicates that information to the nucleus. Current
evidence indicates that AF, and other pathogenic fungi, rely heavily on the UPR to support virulence and
antifungal drug resistance. However, the mechanisms by which this is accomplished are incompletely
understood. The preliminary data in this grant provide evidence for a new mechanism of UPR function that
involves the regulation of cytoplasmic Ca2+ levels in response to two stress conditions that AF must adapt to in
the host: (1) loss of ER homeostasis caused by increased demand on the secretory pathway, and (2) direct
attack by cells of the innate immune system. Since Ca2+ is a potent second messenger, these findings suggest
that the UPR integrates with signaling pathways that decode cytoplasmic Ca2+ signatures into host adaptive
responses. We propose three aims to determine the mechanisms by which AF adapts to these stressors; Aim
1 will establish how the UPR links to Ca2+ signaling during ER stress and the relationship it has to calcineurin
activation and virulence, Aim 2 will identify the mechanism by which cells of the innate immune system trigger
Ca2+ influx into the fungus and elucidate the impact of these events on fungal survival. Lastly, Aim 3 will use
an unbiased approach to delineate the genome-wide transcriptional and translational responses to neutrophil
attack, and their dependency upon Ca2+ signaling. The outcome of this study will reveal new mechanisms of
host adaptation by this fungus, which will pave the way for future therapeutic strategies to augment host
clearance mechanisms.

## Key facts

- **NIH application ID:** 9979741
- **Project number:** 5R01AI123158-05
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** DAVID S ASKEW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $415,286
- **Award type:** 5
- **Project period:** 2016-09-27 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979741

## Citation

> US National Institutes of Health, RePORTER application 9979741, ER stress and calcium in host adaptation of A. fumigatus (5R01AI123158-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9979741. Licensed CC0.

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