This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Aspergillus fumigatus is a saprophytic filamentous fungus that is increasingly becoming a significant opportunistic pathogen in immunocompromised patients. Currently, the mechanisms used by A. fumigatus to survive and cause disease in immunocompromised mammalian hosts is not 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 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. In addition, Dr. Cramer's lab is attempting to identify other mechanisms utilized by this pathogenic mould to adapt to hypoxic microenvironments found at sites of infection. The results of this proposal have potential clinical significance via direct manipulation of oxygen levels at sites of fungal infection, which may enhance the effects of current antifungal drug therapies.
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