Aspergillus fumigatus lives primarily as a saprobe but has become an emerging opportunistic human pathogen with mortality rates reaching 50%. Studies examining population structure between clinical (CL) and environmental (ENV) derived strains have revealed no distinct differentiation. However, these studies have relied on relatively few markers. Similarly, only one study to date has investigated whole genome gene expression response during human temperature growth conditions. This study examined only a single strain of A. fumigatus.
My aim i s to better resolve differences between CL and ENV strains with the intention of gaining insight into the genomic regions and genetic factors influencing pathogenicity. I will accomplish this objective via three main experiments. First, over 200 microsatellite markers, which I have developed, will be used to assess phylogenetic relatedness of CL and ENV strains. With this analysis, I will test the hypothesis that CL and ENV isolates of A. fumigatus are genetically indistinguishable. Second, the same marker set will be used to compare relative levels of diversity between CL and ENV strains. This analysis will be used to identify regions of the CL genome which have been recently positively selected. This study will pinpoint candidate regions for further fine scale mapping with the purpose of revealing novel pathogenicity related genes. Lastly, I will measure genome-wide gene expression differences in CL and ENV strains in response to temperature conditions mimicking soil and the human body. This analysis will allow me to distinguish the genetic and environmental contributions involved in A. fumigatus thermotolerance. The results of this research will increase scientific knowledge concerning A. fumigatus pathogenicity, specifically by more finely resolving population structure, identifying novel genomic regions and genes involved in pathogenicity and identifying unique gene expression response involved in thermotolerance.
Aspergillus fumigatus is an emerging and potentially lethal pathogen to which individuals with vulnerable immune systems are particularly susceptible. Antifungal resistant strains of A. fumigatus have recently appeared, creating new challenges in treating these infections. My research proposal aims to pinpoint genetic factors involved in A. fumigatus infection, while in turn potentially generating novel candidate drug targets.
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