A Wor1-Like Transcription Factor Is Essential for Virulence of Cryptococcus neoformans.


Gti1/Pac2 transcription factors occur exclusively in fungi and their roles vary according to species, including regulating morphological transition and virulence, mating and secondary metabolism. Many of these functions are important for fungal pathogenesis. We therefore hypothesized that one of the two proteins of this family in Cryptococcus neoformans, a major pathogen of humans, would also control virulence-associated cellular processes. Elimination of this protein in C. neoformans results in reduced polysaccharide capsule expression and defective cytokinesis and growth at 37°C. The mutant loses virulence in a mouse model of cryptococcal infection and retains only partial virulence in the Galleria mellonella alternative model at 30°C. We performed RNA-Seq experiments on the mutant and found abolished transcription of genes that, in combination, are known to account for all the observed phenotypes. The protein has been named Required for cytokinesis and virulence 1 (Rcv1).





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Publication Info

Paes, Hugo Costa, Lorena da Silveira Derengowski, Luisa Defranco Ferreira Peconick, Patrícia Albuquerque, Georgios Joannis Pappas, André Moraes Nicola, Fabiana Brandão Alves Silva, Marcelo Afonso Vallim, et al. (2018). A Wor1-Like Transcription Factor Is Essential for Virulence of Cryptococcus neoformans. Frontiers in Cellular and Infection Microbiology, 8. p. 369. 10.3389/fcimb.2018.00369 Retrieved from https://hdl.handle.net/10161/17689.

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James Andrew Alspaugh

Professor of Medicine

The focus of my research is to understand the ways in which microorganisms sense and respond to changes in their environment. As microbial pathogens enter the infected host, dramatic genetic and phenotypic events occur that allow these organisms to survive in this harsh environment. We study the model fungal organism Cryptococcus neoformans to define signal transduction pathways associated with systemic fungal diseases. This pathogenic fungus causes lethal infections of the central nervous system in patients with AIDS and other immunological disorders. In addition to being an important pathogen, C. neoformans displays well-characterized and inducible virulence determinants. It is an outstanding system for dissecting the signaling pathways associated with pathogenicity.

The main techniques used in the lab are those of molecular genetics. We are able to readily mutate C. neoformans genes by homologous recombination. Mutant strains with disruptions in targeted genes are then evaluated in vitro for various phenotypes including altered expression of polysaccharide capsule and melanin. The effects of gene disruption on pathogenicity are also evaluated in animal models of cryptococcal disease. Using these techniques, we have identified a novel G-alpha protein/cAMP-dependent signaling pathway associated with mating and pathogenicity.

This research is complemented by the other investigators in the Duke University Mycology Research Unit. The members of this research community are pursuing studies in fungal pathogenesis, identifying novel antifungal drug targets, and studying the ecology of several medically important fungi.

Keywords: Microbial Pathogenesis
Cryptococcus neoformans
Signal transduction
Fungal mating
G proteins

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