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The Ypd1 phosphorelay protein is a central constituent of fungal two-component signal transduction pathways. Inhibition of Ypd1 in  Saccharomyces cerevisiae  and  Cryptococcus neoformans  is lethal due to the sustained activation of the ‘p38-related’ Hog1 stress-activated protein kinase (SAPK). As two-component signalling proteins are not found in animals, Ypd1 is considered to be a prime antifungal target. However, a major fungal pathogen of humans,  Candida albicans , can survive the concomitant sustained activation of Hog1 that occurs in cells lacking  YPD1 . Here we show that the sustained activation of Hog1 upon Ypd1 loss is mediated through the Ssk1 response regulator. Moreover, we present evidence that  C .  albicans  survives SAPK activation in the short-term, following Ypd1 loss, by triggering the induction of protein tyrosine phosphatase-encoding genes which prevent the accumulation of lethal levels of phosphorylated Hog1. In addition, our studies reveal an unpredicted, reversible, mechanism that acts to substantially reduce the levels of phosphorylated Hog1 in  ypd1Δ  cells following long-term sustained SAPK activation. Indeed, over time,  ypd1Δ  cells become phenotypically indistinguishable from wild-type cells. Importantly, we also find that drug-induced down-regulation of  YPD1  expression actually enhances the virulence of  C .  albicans  in two distinct animal infection models. Investigating the underlying causes of this increased virulence, revealed that drug-mediated repression of  YPD1  expression promotes hyphal growth both within murine kidneys, and following phagocytosis, thus increasing the efficacy by which  C .  albicans  kills macrophages. Taken together, these findings challenge the targeting of Ypd1 proteins as a general antifungal strategy and reveal novel cellular adaptation mechanisms to sustained SAPK activation.

Blocking two-component signalling enhances Candida albicans virulence and reveals adaptive mechanisms that counteract sustained SAPK activation