# Antifungal Immunity and the Mechanism of Fungal Programmed Cell Death

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $653,049

## Abstract

PROJECT SUMMARY
Humans inhale fungal conidia (i.e, vegetative spores) on a daily basis. The ability of the respiratory innate
immune system to prevent germination of inhaled conidia into tissue-invasive hyphae represents a critical
immunologic checkpoint. Using Aspergillus fumigatus, the most common etiologic agent of invasive
aspergillosis, as a model system for human fungal pathogens, we discovered that conidia undergo
programmed cell death with apoptosis-like features during interactions with innate immune cells. This finding
was facilitated by a novel fluorescent reporter of fungal physiology that enables visualization and quantitation
of fungal apoptosis markers, including histone degradation, caspase activation, and DNA fragmentation.
Our work demonstrates that A. fumigatus conidia express an essential and druggable anti-apoptotic protein,
termed Bir1, that counters host induction of apoptosis-like programmed cell death by the action of phagocyte
NADPH oxidase. Genetic and pharmacologic studies demonstrate that Bir1 expression and activity underlie
conidial susceptibility to host apoptosis-like programmed cell death, and in turn, host susceptibility to invasive
aspergillosis. These findings indicate that mammalian fungal immune surveillance exploits a fungal apoptosis-
like programmed cell death pathway to maintain barrier immunity in the lung.
In this collaborative proposal with two co-investigators, we seek to determine the mechanism through which
Bir1 regulates anti-apoptotic activity during fungal-host cell encounters. Our preliminary data support a model
in which Bir1 exerts anti-apoptotic activity via two conserved BIR domains, underlies post-translational
regulation in response to pro-apoptotic stress, regulates candidate fungal caspase-like enzymes as apoptosis
effectors, and demonstrates functional conservation across human pathogenic fungi. Based on these
observations, our model predicts that fungal apoptosis-like programmed cell death is a general feature of
fungal-host cell encounters and central to the establishment of invasive fungal disease. We explore this model
in the following aims: (1) define the functional domains and post-translational regulation of Bir1 critical for
resistance to host induction of apoptosis-like programmed cell death, (2) define the mechanism of Bir1-
mediated resistance to host induction of apoptosis-like programmed cell death, with an emphasis on regulation
of a candidate fungal caspase-like activity, and (3) define the role of apoptosis-like programmed cell death and
Bir1 homologs following Aspergillus nidulans and Candida albicans challenge. The proposed studies are
significant and innovative because they identify a novel mechanism of immune surveillance and demonstrate
that higher eukaryotes can exploit programmed cell death in lower eukaryotes for the purpose of sterilizing
immunity. This work will provide a mechanistic understanding of Bir1 function in regulating host-fungal
encounters. Knowledg...

## Key facts

- **NIH application ID:** 9852568
- **Project number:** 5R01AI139632-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Robert Andrew Cramer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $653,049
- **Award type:** 5
- **Project period:** 2019-01-22 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852568

## Citation

> US National Institutes of Health, RePORTER application 9852568, Antifungal Immunity and the Mechanism of Fungal Programmed Cell Death (5R01AI139632-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9852568. Licensed CC0.

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