EXCEED THE SPACEPROVIDED.Aspergillus fumigatus (Af) is the major cause of invasive aspergillosis (IA), an often-fatal disease in thegrowing population of immunocompromised individuals. Itraconazole and amphotericin B are the onlycurrently available treatments for those cases where invasive hyphal growth escapes the host's innateimmune system. However, their effectiveness in vivo is low and the prognosis for individuals with IA is poor.The search for (At) virulence factors has been problematic because mutations in the obvious candidates donot reduce virulence. Interestingly, the majority of genes that affect pathogenesis slow the rate of hyphalextension, perhaps giving the host more time to mount a defense. Af grows as a mycelium that extendsthrough medium via polarized hyphal growth. This mode of growth requires that new materials be constantlymoved to the growing tip of the hypha. Our laboratory has been involved in elucidating the function of DopA,the founding member of a protein family that is evolutionary conserved fromfungi to mammals. Earlier workfrom our lab indicates that DopA is an essential gene that is involved in protein trafficking.
Specific Aim 1 will test the hypothesis that the ability to establish and maintain highly polarized hyphal growth is a keymechanism for avoidance of innate immunity in immunocompromised patients, and is a major contributingfactor in virulence of filamentous fungal pathogens. Mutations that affect fungal growth will be studied inanimal cell lines. The virulence of dopA mutants will be assessed in the mouse invasive pulmonaryaspergillosis model.
Specific Aim 2 will test the hypothesis that Af DopA (DopeyA) and An DopA proteinsrepresent a novel and essential component of cellular protein trafficking required for polarized cell growth inresponse to environmental signaling. DopA protein will be localized in living cells by using GFP fusions. Therole of DopA in the localization of other known polarity determinants will be investigated. DopA interactingproteins will be identified by a number of methods to elucidate the mechanisms of polar growth. Thisapproach will contribute to an understanding of the molecular mechanisms that link signaling to hyphalgrowth.
Specific Aim 3 will test the hypothesis that Af has a cryptic sexual cycle that can be manipulated todevelop meiotic genetics as a tool for Af. The addition of sexual genetics will be invaluable to investigatorsstudying Aspergillus fumigatus.
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