Aspergillus fumigatus mitochondrial electron transport chain mediates oxidative stress homeostasis, hypoxia responses and fungal pathogenesis.

Abstract

We previously observed that hypoxia is an important component of host microenvironments during pulmonary fungal infections. However, mechanisms of fungal growth in these in vivo hypoxic conditions are poorly understood. Here, we report that mitochondrial respiration is active in hypoxia (1% oxygen) and critical for fungal pathogenesis. We generated Aspergillus fumigatus alternative oxidase (aoxA) and cytochrome C (cycA) null mutants and assessed their ability to tolerate hypoxia, macrophage killing and virulence. In contrast to ΔaoxA, ΔcycA was found to be significantly impaired in conidia germination, growth in normoxia and hypoxia, and displayed attenuated virulence. Intriguingly, loss of cycA results in increased levels of AoxA activity, which results in increased resistance to oxidative stress, macrophage killing and long-term persistence in murine lungs. Thus, our results demonstrate a previously unidentified role for fungal mitochondrial respiration in the pathogenesis of aspergillosis, and lay the foundation for future research into its role in hypoxia signalling and adaptation.

• Authors: Nora Grahl, Taisa Magnani Dinamarco, Sven D Willger, Gustavo H Goldman, Robert A Cramer
• Journal: Molecular microbiology (Mol Microbiol) Vol. 84 Issue 2 Pg. 383-99 (Apr 2012) ISSN: 1365-2958 [Electronic] England
• PMID: 22443190 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Blackwell Publishing Ltd.

Chemical References

• Electron Transport Chain Complex Proteins
• Virulence Factors

Topics

• Anaerobiosis
• Animals
• Aspergillosis (microbiology, mortality)
• Aspergillus fumigatus (genetics, growth & development, pathogenicity, physiology)
• Cell Line
• Disease Models, Animal
• Electron Transport
• Electron Transport Chain Complex Proteins (genetics, metabolism)
• Gene Knockout Techniques
• Homeostasis
• Macrophages (immunology, microbiology)
• Mice
• Models, Biological
• Models, Molecular
• Oxidative Stress
• Spores, Fungal (growth & development)
• Survival Analysis
• Virulence
• Virulence Factors (metabolism)