A Major Role for Capsule-Independent Phagocytosis-Inhibitory Mechanisms in Mammalian Infection by Cryptococcus neoformans

SummaryThe antiphagocytic polysaccharide capsule of the human fungal pathogen Cryptococcus neoformans is a major virulence attribute. However, previous studies of the pleiotropic virulence determinant Gat201, a GATA family transcription factor, suggested that capsule-independent antiphagocytic mechanisms exist. We have determined that Gat201 controls the mRNA levels of ∼1100 genes (16% of the genome) and binds the upstream regions of ∼130 genes. Seven Gat201-bound genes encode for putative and known transcription factors—including two previously implicated in virulence—suggesting an extensive regulatory network. Systematic analysis pinpointed two critical Gat201-bound genes, GAT204 (a transcription factor) and BLP1, which account for much of the capsule-independent antiphagocytic function of Gat201. A strong correlation was observed between the quantitative effects of single and double mutants on phagocytosis in vitro and on host colonization in vivo. This genetic dissection provides evidence that capsule-independent antiphagocytic mechanisms are pivotal for successful mammalian infection by C. neoformans.

► C. neoformans inhibits its own phagocytosis by activating a transcriptional program
► The vital transcription factor Gat201 binds ∼130 promoters and regulates ∼1100 genes
► Two key targets of Gat201, GAT204 and BLP1, synergistically inhibit phagocytosis
► Phagocytosis of mutants in vitro inversely correlates with fitness during infection