Abstract

The ability for cells to maintain homeostasis in the presence of extracellular stress is essential for their survival. Stress adaptations are especially important for microbial pathogens to respond to rapidly changing conditions, such as those encountered during the transition from the environment to the infected host. Many fungal pathogens have acquired the ability to quickly adapt to changes in extracellular pH to promote their survival in the various microenvironments encountered during a host infection. For example, the fungus-specific Rim/Pal alkaline response pathway has been well characterized in many fungal pathogens, including Cryptococcus neoformans However, alternative mechanisms for sensing and responding to host pH have yet to be extensively studied. Recent observations from a genetic screen suggest that the C. neoformans sterol homeostasis pathway is required for growth at elevated pH. This work explores interactions among mechanisms of membrane homeostasis, alkaline pH tolerance, and Rim pathway activation. We find that the sterol homeostasis pathway is necessary for growth in an alkaline environment and that an elevated pH is sufficient to induce Sre1 activation. This pH-mediated activation of the Sre1 transcription factor is linked to the biosynthesis of ergosterol but is not dependent on Rim pathway signaling, suggesting that these two pathways are responding to alkaline pH independently. Furthermore, we discover that C. neoformans is more susceptible to membrane-targeting antifungals under alkaline conditions, highlighting the impact of microenvironmental pH on the treatment of invasive fungal infections. Together, these findings further connect membrane integrity and composition with the fungal pH response and pathogenesis.IMPORTANCE The work described here further elucidates how microorganisms sense and adapt to changes in their environment to establish infections in the human host. Specifically, we uncover a novel mechanism by which an opportunistic human fungal pathogen, Cryptococcus neoformans, responds to increases in extracellular pH in order to survive and thrive within the relatively alkaline environment of the human lung. This mechanism, which is intimately linked with fungal membrane sterol homeostasis, is independent of the previously well-studied alkaline response Rim pathway. Furthermore, this ergosterol-dependent alkaline pH response is present in Candida albicans, indicating that this mechanism spans diverse fungal species. These results are also relevant for novel antimicrobial drug development as we show that currently used ergosterol-targeting antifungals are more active in alkaline environments.

Highlights

  • The ability for cells to maintain homeostasis in the presence of extracellular stress is essential for their survival

  • Recent forward genetic screen identified two elements of the C. neoformans sterol homeostasis pathway, the Sre1 transcription factor and its activating protease Stp1, as proteins required for growth of this pathogenic fungus at an alkaline pH [15]

  • Data presented in this study identified the sterol homeostasis pathway as a unique mechanism that responds to alkaline pH in a Rim-independent way (Fig. 7)

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Summary

Introduction

The ability for cells to maintain homeostasis in the presence of extracellular stress is essential for their survival. We uncover a novel mechanism by which an opportunistic human fungal pathogen, Cryptococcus neoformans, responds to increases in extracellular pH in order to survive and thrive within the relatively alkaline environment of the human lung This mechanism, which is intimately linked with fungal membrane sterol homeostasis, is independent of the previously well-studied alkaline response Rim pathway. The shift of a fungal pathogen from an acidic external environment to the neutral/alkaline pH of the mammalian host is associated with the activation of the fungus-specific Rim/Pal signaling pathway, triggering cellular changes important for survival under these new conditions These changes include alterations in the cell wall, often accompanied by larger morphological transitions that promote host colonization. Reduced ergosterol content in membranes has been linked to salt stress sensitivity in Saccharomyces cerevisiae [12, 13] and to aberrant V-ATPase regulation of pH gradients in Candida albicans [13, 14]

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