A trade-off between proliferation and defense in the fungal pathogen Cryptococcus at alkaline pH is controlled by the transcription factor GAT201

Author Summary Micro-organisms face trade-offs in adapting to their environments. For example, pathogens adapting to host niches must balance investing in proliferation – reproduction and growth – against investing in defense against the host immune system. Cryptococcus neoformans is an encapsulated fungal pathogen that can infect human airways and, in immunocompromised people, can move to the brain to cause life-threatening meningitis. It is well appreciated that fungal persistence in these sites depends on production of a sugar capsule that surrounds the cell, hiding it from host detection. However, in both the lung and brain, fungal proliferation through budding is also a major driver of pathogenesis: both cryptococcal pneumonia and meningitis are characterised by high yeast burden. This presents a trade-off between production of a metabolically costly capsule and cellular proliferation. The regulators of Cryptococcus proliferation are poorly understood, as they are distinct from other model yeasts at the level of cell cycle and morphogenesis. In this work, we study this trade off growing Cryptococcus under conditions that approximate the alkaline surface of human airways, and that restrict fungal growth. We identify a GATA-like transcription factor, Gat201, and its target, Gat204, that positively regulate capsule production and negatively regulate proliferation. The GAT201 pathway is conserved within pathogenic fungi but lost in other model yeasts. Together our findings reveal how a fungal pathogen regulates the balance between defense and proliferation and highlight the need for improved understanding of proliferation in non-model systems.