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Maintenance of hyphal polarity by DopA protein and its role in Aspergillus pathogenesis |
Co-P.I. Bruce Miller
Abstract |
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Aspergillus fumigatus (Af) is the major cause of invasive aspergillosis (IA), an often-fatal disease in the growing population
of immunocompromised individuals. Itraconazole and amphotericin B are the only currently available treatments for those cases
where invasive hyphal growth escapes the host's innate immune system. However, their effectiveness in vivo is low and the
prognosis for individuals with IA is poor. The search for (Af) virulence factors has been problematic because mutations in the
obvious candidates do not reduce virulence. Interestingly, the majority of genes that affect pathogenesis slow the rate of
hyphal extension, perhaps giving the host more time to mount a defense. Af grows as a mycelium that extends through medium via
polarized hyphal growth. This mode of growth requires that new materials be constantly moved 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
evolutionarily conserved from fungi to mammals. Earlier work from 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 key mechanism for avoidance of innate immunity in immunocompromised patients, and is a major
contributing factor in virulence of filamentous fungal pathogens. Mutations that affect fungal growth will be studied in
animal cell lines. The virulence of dopA mutants will be assessed in the mouse invasive pulmonary aspergillosis model.
Specific Aim 2 will test the hypothesis that Af DopA (DopeyA) and An DopA proteins represent a novel and essential component
of cellular protein trafficking required for polarized cell growth in response to environmental signaling. DopA protein will
be localized in living cells by using GFP fusions. The role of DopA in the localization of other known polarity determinants
will be investigated. DopA interacting proteins will be identified by a number of methods to elucidate the mechanisms of polar
growth. This approach will contribute to an understanding of the molecular mechanisms that link signaling to hyphal growth.
Specific Aim 3 will test the hypothesis that Af has a cryptic sexual cycle that can be manipulated to develop meiotic genetics
as a tool for Af. The addition of sexual genetics will be invaluable to investigators studying Aspergillus fumigatus.
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