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down-regulated as the morphological conversion to the mycelial form progresses.

Histoplasma as a Model System

Among the fungi, only a few primary pathogens cause systemic mycoses, and among those, H. capsulatum has received the most research attention in terms of biology, biochemistry, and molecular genetics. Historically, the mycelia–yeast transition and the ability of yeasts to destroy macrophages have been the areas of primary focus. With the development of molecular genetic tools such as freely replicating plasmids, reporter genes, and gene disruption strategies, it is now possible to probe this organism's fascinating biology with genetic precision and functional proof. It is also likely that many of the lessons learned from H. capsulatum will be applicable to the other dimorphic fungal pathogens, most of which are closely related and cause similar clinical syndromes. The existence of a morphological form dedicated to parasitism provides a highly visible target in the hunt for genes and regulatory mechanisms that are most likely to be involved in fungal pathogenesis.

This work was supported by Public Health Service Grants AI25584 (to W.E.G.), AI07172 (to Washington University), and HL07317 (to Washington University). W.E.G. is a recipient of the Burroughs–Wellcome Fund Scholar Award in Molecular Pathogenic Mycology.

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