Abstract
Proliferation and host evasion are critical processes to understand at a basic biological level for improving infectious disease treatment options. The human fungal pathogen Cryptococcus neoformans causes fungal meningitis in immunocompromised individuals by proliferating in cerebrospinal fluid. Current antifungal drugs target “virulence factors” for disease, such as components of the cell wall and polysaccharide capsule in C. neoformans. However, mechanistic links between virulence pathways and the cell cycle are not as well studied. Recently, cell-cycle synchronized C. neoformans cells were profiled over time to identify gene expression dynamics (Kelliher et al., PLoS Genet 12(12):e1006453, 2016). Almost 20% of all genes in the C. neoformans genome were periodically activated during the cell cycle in rich media, including 40 genes that have previously been implicated in virulence pathways. Here, we review important findings about cell-cycle-regulated genes in C. neoformans and provide two examples of virulence pathways—chitin synthesis and G-protein coupled receptor signaling—with their putative connections to cell division. We propose that a “comparative functional genomics” approach, leveraging gene expression timing during the cell cycle, orthology to genes in other fungal species, and previous experimental findings, can lead to mechanistic hypotheses connecting the cell cycle to fungal virulence.
Highlights
Human fungal pathogens cause more than a million lifethreatening illnesses each year (Brown et al 2012)
We investigate two virulence pathways in C. neoformans that contain genes that are periodically expressed during the cell cycle
Our recent publication describes in detail how different time series experiments for C. neoformans and S. cerevisiae cells are aligned on a common “cell-cycle time” axis using the CLOCCS algorithm (Orlando et al 2007, 2009) (Kelliher et al 2016: S1 File). According to this common timeline, origin-firing genes are transcribed in early G1 phase during each cell cycle (Guo et al 2013; Kelliher et al 2016). These findings suggest a common function for MCM genes in S. cerevisiae and in C. neoformans
Summary
Human fungal pathogens cause more than a million lifethreatening illnesses each year (Brown et al 2012). After identifying the expression timing of the virulence genes of interest, we predict roles of these genes during the cell cycle by incorporating the previous genetic and cell biological findings about gene function and by comparing to sequence orthologs in S. cerevisiae.
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