ALCOHOL FERMENTATION AND PATHOGENESIS IN RESPONSE TO HYPOXIA IN A FUMIGATUS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Aspergillus fumigatus is a saprophytic filamentous fungus that is the most frequent causal agent of invasive opportunistic mould infections in immunocompromised patients. Currently, the mechanism used by A. fumigatus to survive and cause disease in immunocompromised hosts is not well understood. During mammalian pathogenesis, all pathogenic microbes are exposed to rapidly changing oxygen levels. Oxygen is the critical electron acceptor in aerobic respiration and organisms must possess alternative mechanisms to deal with low oxygen (hypoxic) conditions found at sites of infection in vivo. Dr. Cramer's hypothesis is that A. fumigatus utilizes an alcohol fermentation pathway to survive inflammatory responses found in vivo in pulmonary invasive aspergillosis. This hypothesis is founded on preliminary data from metabolomics studies of A. fumigatus infected murine broncheoalveolar lavages showing the production of ethanol in vivo during fungal infections. Dr. Cramer's lab is exploring whether this alcohol fermentation pathway is important for A. fumigatus to cause disease by creating genetic mutants of A. fumigatus deficient in their ability to respond to low oxygen conditions via the use of an alcohol fermentation pathway. Dr. Cramer's lab has identified the genes and generated mutants deficient in these genes, which are involved in alcohol fermentation in A. fumigatus. In addition, Dr. Cramer is attempting to identify additional mechanisms utilized by this pathogenic mould to adapt to hypoxic microenvironments found at sites of infection. They have identified a novel transcription factor, SrbA, which is mediating A. fumigatus hypoxia adaptation, azole drug resistance, and fungal virulence. The results of this proposal have potential clinical significance via direct manipulation of oxygen levels at sites of fungal infection and also the potential to generate increased efficacy of current antifungal drugs.