Cellular Mechanisms Governing an Invasive Aspergillosis Virulence Factor

Garvey, Graeme

Abstract

Secondary metabolites produced by filamentous fungi represent an enormous reservoir of natural chemical diversity. These non-essential compounds are often employed by the producing fungi in defense and pathogenesis. Impairment of secondary metabolite production in the opportunistic human pathogen Aspergillus fumigatus by deletion of a global regulatory gene, laeA, reduces this organism's virulence. The gene product of laeA is part of a large nuclear regulator complex that links light responsive development and secondary metabolism in Aspergilli and other pathogenic genera. The silencing of secondary metabolite production, decrease of spore production, and reduced virulence In AlaeA strains makes LaeA an excellent target for reducing the mortality rates of IA and other fungal diseases. The mechanism of LaeA regulation of secondary metabolism has remained elusive. The overall goal of this proposal is to elucidate the mechanism of LaeA function.
Specific aims to achieve this goal include 1) to further biochemically characterize the methyltransferase activity of this gene product. 2) to identify the chromatin protein interactors involved with LaeA regulation of gene clusters 3) to develop and implement a forward genetics screen to identify potential LaeA targets required for secondary metabolite cluster expression. Relevance: Aspergillus fumigatus, a ubiquitous environmental fungus, is the primary causal agent of invasive aspergillosis. Current treatments with antifungal agents is often ineffective with invasive aspergillosis mortality rates still unacceptably high, it is therefore necessary to continue targeting other virulence attributes of A. fumigatus, such as LaeA governing of secondary metabolite production. Knowledge gained from this study could benefit future efforts in developing effective treatments of fungal infections.