Abstract

Organisms face trade-offs in adapting to their environments, to balance competing demands on metabolism and gene expression. For example, pathogens adapting to host niches must trade off investing in proliferation against investing in defense against the host immune system. Cryptococcus is a fungal pathogen whose virulence relies on proliferation in otherwise privileged host sites, and also on synthesising a defensive yet metabolically costly polysaccharide capsule. Regulatory pathways required for Cryptococcus virulence include a GATA-like transcription factor, Gat201, that operates in both capsule-dependent and capsule-independent ways. Here we show that GAT201 is part of a negative regulatory pathway that limits survival. RNA-seq analysis found strong induction of GAT201 expression within minutes of transfer to host-like media at alkaline pH. Under these conditions, wild-type Cryptococcus cells produce capsule but do not bud or maintain viability, while gat201∆ cells make buds and maintain viability yet fail to produce capsule. GAT201 is required for transcriptional upregulation of a specific set of genes in host-like media, the majority of which are direct Gat201 targets. Evolutionary analysis shows that Gat201 is conserved within pathogenic fungi but lost in model yeasts. This work identifies the Gat201 pathway as controlling a trade-off between proliferation and defense. The in vitro assays established here will allow characterisation of the mechanisms of action of the pathway. Together, our findings urge improved understanding of fungal proliferation as a driver of fungal pathogenesis.