A trade-off between proliferation and defense in the fungal pathogen Cryptococcus at alkaline pH is controlled by the...

Cryptococcus is a fungal pathogen whose virulence relies on proliferation in and dissemination to host sites, and on synthesis of a defensive yet metabolically costly polysaccharide capsule. Regulatory pathways required for Cryptococcus virulence include a GATA-like transcription factor, Gat201, that regulates Cryptococcal virulence in both capsule-dependent and capsule-independent ways. Here we show that Gat201 is part of a negative regulatory pathway that limits fungal survival at alkaline pH. RNA-seq analysis found strong induction of GAT201 expression within minutes of transfer to RPMI media at alkaline pH. Microscopy, growth curves, and colony forming unit assays show that in RPMI at alkaline pH wild-type Cryptococcus neoformans yeast cells produce capsule but do not bud or maintain viability, while gat201Δ cells make buds and maintain viability, yet fail to produce capsule. GAT201 is required for transcriptional upregulation of a specific set of genes, the majority of which are direct Gat201 targets. Evolutionary analysis shows that Gat201 is in a subfamily of GATA-like transcription factors that is conserved within pathogenic fungi but absent in model yeasts. This work identifies the Gat201 pathway as controlling a trade-off between proliferation and production of defensive capsule. The assays established here will allow characterisation of the mechanisms of action of the Gat201 pathway. Together, our findings urge improved understanding of the regulation of proliferation as a driver of fungal pathogenesis.