Fungal Morphology in Resistance to Calcineurin Inhibitors and Host - Pathogen Interactions

Date

2020

Authors

Vellanki, Sandeep

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Abstract

Fungal dimorphism is the ability of a fungus to switch between budding yeast and filamentous morphology. Fungal morphology is critical in adapting to diverse environments, drug resistance, and pathogenesis. One such dimorphic fungus is Mucor circinelloides (Mucor), a natural mold and the causative agent of mucormycosis. A protein phosphatase calcineurin promotes filamentous growth in Mucor. When calcineurin function is blocked by inhibitors such as FK506 Mucor grows as yeast. The mutants lacking calcineurin exhibit yeast morphology and are less virulent which makes calcineurin an attractive target for the treatment of mucormycosis. The first part of the study elucidates a novel mechanism by which Mucor develops resistance to calcineurin inhibitors. Mutations in an amino acid permease gene bycA bypass the requirement of calcineurin enabling Mucor to continue to grow in the hyphal form even in the presence of calcineurin inhibitors. The second part of the study solves the conundrum whether it is Mucor morphology or calcineurin that primarily contributes to host-pathogen interactions in mucormycosis. Calcineurin independent of its role in morphology is required for Mucor inhibition of phagosome maturation in macrophages, damage to the endothelium, and production of a host pro-angiogenic protein basic Fibroblast Growth Factor (FGF) -2. The final part elucidates how a hyphal specific toxin from Candida albicans (the causative agent of candidiasis) regulates a host FGF-2 response. Treatment with FGF-2 increases mortality in a systemic murine model of candidiasis. Therefore, the study elucidates how morphology specific fungal factors are involved in drug resistance and host-pathogen interactions in mucormycosis and candidiasis.

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Keywords

Angiogenesis, Candidiasis, Drug resistance, Fungi, Morphology, Mucormycosis

Citation

Department

Integrative Biology