Analysis of the Fungal Virulence of Cryptococcus and Exploration of Novel Antifungals Against Cryptococcosis
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Cryptococcosis is one of the leading causes of the deaths among AIDS patients. The high mortality rates of cryptococcosis are mainly due to inadequate information of its major causative agent Cryptococcus neoformans and the limitations of current therapies. Cryptococcus neoformans is an unconventional dimorphic fungus that can grow either as a yeast or in a filamentous form. To study this dimorphism that is critical to the pathogenicity of many fungi, we constructed the congenic a and α strains for XL280(α), a strain with robust ability to undergo the yeast-hyphal transition. We compared the congenic strains in different in vivo models and found they are equivalent in virulence. Furthermore, deletion or overexpression of a known transcription factor Znf2 in XL280 abolished or enhanced filamentation and biofilm formation, consistent with its established role. Therefore, the congenic strains provide a new resource for the study of morphogenesis and the related virulence of Cryptococcus. Meanwhile, we searched for novel antifungals by screening of a clinical compound library. Two hits from the screen, the antibiotic polymyxin B and the antidepressant sertraline are all potently fungicidal against Cryptococcus. Polymyxin B works synergistically with the azoles both in vitro and in vivo, thus it may serve as an adjunctive therapy with fluconazole in clinic. Our investigation on sertraline has implicated its unique advantage in treating cryptococcal infections since it is able to traverse the blood brain barrier and reduce the fungal burden in brains. We further examined the fungal target of sertraline and found that this compound inhibits the fungal protein synthesis. Taken together, the studies in this thesis facilitate further research on the pathogenesis of Cryptococcus and provide new antifungal drug candidates with clinical value.
Zhai, Bing (2014). Analysis of the Fungal Virulence of Cryptococcus and Exploration of Novel Antifungals Against Cryptococcosis. Doctoral dissertation, Texas A & M University. Available electronically from