Human disease caused by fungi is increasing in frequency and clinical outcomes remain unacceptably poor due in part to a limited spectrum of treatment options. New insights into fungal pathogenesis mechanisms has great potential to uncover new therapeutic options for these devastating diseases. Our laboratory is investigating how the most common causal agent of human airborne fungal infections, Aspergillus fumigatus, adapts and grows in in vivo microenvironments generated during the fungal-host interaction. We have observed that significant oxygen depletion, hypoxia, occurs at sites of A. fumigatus infection in the lung. The ramifications of hypoxia on obligate aerobic fungal metabolism, both from the perspective of in vivo fungal growth and the production of fungal metabolites that influence the innate immune response, are largely unknown. Using a combination of genomics, fungal molecular genetics, animal models of fungal disease, and immunology we have begun to unravel the impact of hypoxia on outcomes of invasive pulmonary aspergillosis. We have observed that fungal metabolic responses to hypoxia are largely interconnected with an increased demand for iron uptake that directly influences metabolic pathways requiring both oxygen and iron as co-factors such as ergosterol, heme, and cell wall biosynthesis. These responses are regulated in part by 2 transcription factors with sequence similarity to the sterol regulatory element binding protein family (SREBPs). In turn, these metabolic pathways are not only essential for fungal growth under hypoxia, but also for the production of pathogen associated molecular patterns (PAMPs) that influence the innate immune response to the invading fungus. Our data suggest that hypoxia alters the composition of the fungal cell wall resulting in increased production of pro-inflammatory cytokines from host effector cells that may cause host tissue damage. Taken together, our data suggest that manipulation of in vivo oxygen levels may be a promising strategy to augment existing antifungal drug treatment through manipulation of fungal metabolism and improve patient outcomes from these increasingly common human diseases.
Full conference title:
27th Fungal Genetics Conference
- Fungal Genetics Conference 27th (2013)