# Evolution of Aspergillus fumigatus virulence

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2024 · $555,374

## Abstract

Project Summary. Fungal mediated disease progression is highlighted by populations of fungal cells that form
a community referred to as a biofilm. For therapeutic success, contemporary antifungal therapies must be
effective at the site of infection in the context of an established fungal biofilm. Critically, it is now clear that
emergent properties arise from fungal biofilms that directly alter virulence, disease progression, and antifungal
drug susceptibility. However, the mechanisms through which filamentous fungal biofilm emergent properties
impact virulence, disease progression, and antifungal susceptibility remain a significant knowledge gap. The
long-term goal of this project is focused on defining the molecular mechanisms of Aspergillus fumigatus biofilm
mediated disease progression mechanisms to inform contemporary and novel therapeutic approaches. In the
prior funding period, we made important progress that surprisingly revealed heterogeneity in A. fumigatus
biofilm morphology across clinical isolates. Differences in biofilm morphology altered virulence and disease
progression in vivo in murine models of aspergillosis. We discovered that long term growth in a low oxygen
environment gives rise to a biofilm morphology we termed H-MORPH and that a novel fungal specific gene
cluster that contains a protein with unknown function was sufficient for H-MOPRH formation. Significantly, we
identified H-MORPH clinical isolates from both acute invasive aspergillosis patients and patients with chronic
aspergillosis, suggesting H-MORPH can arise in human disease. We observed that H-MOPRH occurs in vivo
in a murine model of invasive pulmonary aspergillosis and contributes to worse disease outcomes compared to
the contrasting N-MORPH isolates. In aim 1, we will define the genetic pathway(s) that regulate A. fumigatus
the development of this unique population level morphotype utilizing the newly discovered biofilm architecture
factor (baf) gene family as a tool to dissect the underlying mechanisms. In aim 2, we will define the differences
in fungal metabolism that underly N-MORPH and H-MORPH morphotypes and test the hypothesis that H-
MORPH biofilms are carbon catabolite de-repressed which leads to increased fitness in vivo. In aim 3, we test
the hypothesis that H-MORPH strain metabolism is immune modulatory through alterations in fungal pathogen
associated molecular pattern exposure. Taken together, our proposed studies will fill significant knowledge
gaps related to the discovery of distinct A. fumigatus morphotypes that directly impact virulence. Advancing our
understanding of this knowledge gap is expected to lay the foundation for new diagnostic and therapeutic
strategies to combat highly virulent and drug resistant strains of this important human fungal pathogen.

## Key facts

- **NIH application ID:** 10886126
- **Project number:** 5R01AI130128-07
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Robert Andrew Cramer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $555,374
- **Award type:** 5
- **Project period:** 2017-09-25 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886126

## Citation

> US National Institutes of Health, RePORTER application 10886126, Evolution of Aspergillus fumigatus virulence (5R01AI130128-07). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10886126. Licensed CC0.

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