# Environmental Oxygen Transitions and Aspergillosis Disease Progression

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2020 · $529,372

## Abstract

Project Summary.
Invasive aspergillosis (IA) is a major cause of infectious morbidity and mortality in immune compromised
patients, particularly those with acute leukemia, hematopoietic cell transplantation, and recipients of chronic
corticosteroid therapy for graft versus host disease and autoimmunity. Despite recent advances in antifungal
therapies, it remains poorly understood which fungal and host factors are critical for disease progression after
establishment of infection in the lung. We have made 2 fundamental observations toward narrowing this
knowledge gap. First, the causative agent of IA, Aspergillus fumigatus, interacts with host tissue to generate a
dynamic oxygen microenvironment at the site of infection. Second, A. fumigatus adapts to established infection
microenvironments by exhibiting infection site-specific metabolic flexibility that is critical for fungal virulence.
We recently termed these adaptations “disease progression factors” (DPFs) because they are essential for the
progression of invasive disease and relatively undefined in the context of human fungal infections. An exciting
recent discovery is the previously unappreciated role of the fungal oxygen response genetic network, which
includes the DPFs, SrbA, SrbB and CreA, in responses to transitions in oxygen tension. Our recent data lead
us to hypothesize that this oxygen response network regulates the production of specific metabolites that
promote and support fungal disease progression. A major effector of this genetic network, an unstudied fungal
alanine aminotransferase alaA, is the focus of mechanistic studies in Aim 1 of this proposal. We propose a
model whereby alaA functions as key regulator of metabolic transitions required for adaptation to oxygen
fluctuations during fungal disease progression. In aim 2, we build off a novel genetic screen which has
identified four new unstudied fungal transcription factors that are critical for the response to oxygen tension
fluctuations. We have named these new genes ortA-D for oxygen responsive fungal transcription factors. An
innovation to our approach to test our hypotheses and models is the incorporation of in vivo imaging of the
infection site microenvironment during disease progression that is revealing new insights into fungal form and
function in an established infection. Consequently, at the conclusion of these studies, we will have defined new
molecular mechanisms of fungal fitness in established infection environments that are expected to reveal new
therapeutic opportunities to improve disease outcomes for these too often lethal invasive mold infections.

## Key facts

- **NIH application ID:** 9928362
- **Project number:** 5R01AI146121-02
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Robert Andrew Cramer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $529,372
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928362

## Citation

> US National Institutes of Health, RePORTER application 9928362, Environmental Oxygen Transitions and Aspergillosis Disease Progression (5R01AI146121-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9928362. Licensed CC0.

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