Modelling the Regulation of Thermal Adaptation in Candida albicans, a Major Fungal Pathogen of Humans

Abstract

Eukaryotic cells have evolved mechanisms to sense and adapt to dynamic environmental changes. Adaptation to thermal insults, in particular, is essential for their survival. The major fungal pathogen of humans, Candida albicans , is obligately associated with warm-blooded animals and hence occupies thermally buffered niches. Yet during its evolution in the host it has retained a bona fide heat shock response whilst other stress responses have diverged significantly. Furthermore the heat shock response is essential for the virulence of C. albicans . With a view to understanding the relevance of this response to infection we have explored the dynamic regulation of thermal adaptation using an integrative systems biology approach. Our mathematical model of thermal regulation, which has been validated experimentally in C. albicans , describes the dynamic autoregulation of the heat shock transcription factor Hsf1 and the essential chaperone protein Hsp90. We have used this model to show that the thermal adaptation system displays perfect adaptation, that it retains a transient molecular memory, and that Hsf1 is activated during thermal transitions that mimic fever. In addition to providing explanations for the evolutionary conservation of the heat shock response in this pathogen and the relevant of this response to infection, our model provides a platform for the analysis of thermal adaptation in other eukaryotic cells.

Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs

“…In C. albicans, HSP90 transcript levels increase dramatically on thermal upshifts 13 , but Hsp90 protein levels do not increase to the same extent. Translational regulation in heat shocked Drosophila cells was reported by Lindquist three decades ago 2 .…”

“…Hsf1 is rapidly phosphorylated and then dephosphorylated after a 30-42°C heat shock in C. albicans 13 , suggesting regulation via a negative feedback loop. Almost three decades ago Lindquist 2,50 and Didomenico et al 51 postulated that feedback components down-regulate the heat shock response.…”

“…Furthermore, a physical interaction between Hsp90 and Hsf1 has been confirmed by co-immunoprecipitation (Leach et al, unpublished). Therefore, Hsp90-mediated repression of Hsf1 is released following heat shock, Hsf1 becomes activated, and this leads to a transcriptionally mediated increase in Hsp90 levels 13 . This response is then down-regulated when excess Hsp90 binds to Hsf1.…”

“…More recently Leach and colleagues 13 used an ODE (ordinary differential equation) model to investigate the dynamics of the Hsf1-Hsp90 autoregulatory loop (Figure 2). The model focuses on the Hsp90-Hsf1 interaction because the available data suggest that Hsp90 is the main chaperone that represses Hsf1 13,59 .…”

“…Nevertheless, this response is strongly conserved in C. albicans and heat shock adaptation is essential for its virulence 10,12 . This reflects the fact that the "heat shock" apparatus is essential for cellular adaptation to the subtle or gradual thermal transitions that organisms often experience in the wild, not just to the acute temperature up-shifts that experimentalists tend to examine in the laboratory 13 . In particular, the strong conservation of Hsp90 attests to the fundamental importance of the cellular functions executed by this essential chaperone in eukaryotic cells.…”