The clinical relevance of invasive fungal infection has greatly increased since the second half of the twentieth century. The rate of fungal bloodstream infections in the United States tripled between 1979 and 2000, and continues to rise through present day. This significant increase in infection rate is due to rapid growth the population of immunosuppressed individuals as a result of chemotherapy, anti-rejection therapy during organ transplantation, and HIV/AIDS. The pathogenic fungi Candida albicans, Aspergillus fumigatus, and Rhizopus oryzae are responsible for 90% of all invasive fungal infections and have significant mortality rates that range from 30% to 95%.
The successful clearance of a fungal infection requires the combined activity of antifungal therapy and the host immune system. Mortality associated with fungal infections has declined only slightly despite the introduction of new, more potent antifungal agents with less toxic side-effects, indicating that alternative therapeutic approaches are necessary. One such approach would be to combine current antifungal agents with therapy that enhances the host immune response to fungal infections. Augmenting the host's ability to eliminate a pathogen requires a sophisticated understanding, at the molecular level, of the host-pathogen interaction. It is in this area that there is inadequate scientific information.
There are no standard vaccines that exist for preventing fungal infections. Furthermore, fungi are eukaryotes that share many of the same biological processes as humans, and therefore some antifungal drugs cause toxicity when used therapeutically. Hence, there exists a significant need to develop broad-spectrum antifungal preventive and/or treatment strategies. With the long-term goal of identifying novel preventative and/or therapeutic targets to combat invasive fungal infections, the work proposed in this application will focus on understanding the complex interaction between pathogenic fungi and the host, with a focus on Candida spp., Aspergillus spp. and species in the order Mucorales (which cause mucormycosis).
Our central hypothesis is that omics-based approaches as applied to the study of pathogenic fungal-host interactions will enable us to define commonalities as well as key differences among these organisms and the responses they elicit in the host that can ultimately be exploited in the design of novel anti-fungal therapies. To this end, we will perform a comprehensive comparative genome analysis on the entire collection of genome sequences for these strains to define potential therapeutic targets. We will also perform RNA-seq on infected tissues from several, well-established, in vitro models of candidiasis, aspergillosis, and mucormycosis. Utilizing advanced technologies to achieve extremely deep sequencing coverage, this analysis will allow us to determine core host responses to each of these phylogenetically distinct fungi as well as fungus-specific responses.