Like most filamentous fungi, Aspergillus fumigatus produces a wide-array of primary and secondary metabolites that may be secreted into the host environment during opportunistic fungal infections. Thus, these metabolites have the potential to affect host immune responses and alter the outcome of the fungal-host interaction. Research on metabolites produced by A. fumigatus has largely focused on the role of gliotoxin, a potent immunosuppressant secondary metabolite that has been detected in vivo in invasive pulmonary aspergillosis (IPA) patients. Several recent studies have begun to directly elucidate the role of gliotoxin in IPA, utilizing specific gene-replacement mutants in the gliotoxin biosynthesis pathway and experimental murine models of IPA. Results from these studies suggest that gliotoxin is not required for IPA in murine models utilizing cyclophosphamide for immunosuppression, but does play a substantial role when hydrocortisone is utilized as the immunosuppressive agent. Thus, the condition of the patient’s immune system seems to be the primary determining factor for whether gliotoxin plays a critical role in IPA. Yet, an understanding of the effects of gliotoxin on the host immune response is still not precisely known. In addition to secondary metabolites, byproducts of primary metabolism can also be secreted into the host milieu and potentially affect host defense responses. We have utilized 1H-NMR metabolite profiling of broncheoalveolar lavage fluid to identify byproducts of fungal primary metabolism in vivo in a murine model of IPA. Identification of fungal-specific metabolites gives clues to the important biochemical pathways utilized by the fungus during invasive growth in a mammalian host. In this presentation, we will discuss the potential role of gliotoxin in invasive pulmonary aspergillosis, and present preliminary data on the potential role of specific aspects of primary metabolism in allowing A. fumigatus to survive in immunocompromised mammalian lungs.
Full conference title:
3rd Advances Against Aspergillosis
- AAA 3rd (2008)