In vivo Hypoxia and Aspergillus fumigatus pathogenesis Aspergillus fumigatus is a ubiquitous mold found in soil and organic debris that is currently the most frequent cause of airborne invasive fungal infections in immunocompromised individuals. In this study the hypothesis that hypoxia is a stress faced in vivo by A. fumigatus and that the ability to sense adapt to and grow in hypoxic conditions is a virulence attribute of this human fungal pathogen was tested. Utilizing specific staining in 3 clinically relevant murine models it was shown for the first time that hypoxic microenvironments occur at sites of A. fumigatus infection arguing that A. fumigatus has to be able to adapt to these oxygen limited conditions in order to cause disease. In this context a SREBP ortholog was identified and characterized. Importantly the SREBP null mutant was unable to grow in hypoxia and virtually avirulent. Interestingly oxygen sensing and hypoxia adaptation mechanisms can be identified in other fungi suggesting an important role for these mechanisms for fungal biology and virulence. In addition it was found that A. fumigatus utilizes ethanol (EtOH) fermentation in vivo and that this pathway is induced in in vitro hypoxia. While fermentation was shown to not be essential for growth in hypoxia and fungal virulence it was found that loss of the alcohol dehydrogenase involved in EtOH fermentation under hypoxic conditions resulted in significant changes in the host immune response.