Effects of antifungals and long-term macrophage exposure on Candida species : mode of action and fungal response

Pathogenic fungi of humans and plants are an important, yet underestimated problem in the medical care system and in agriculture. Still, only few treatment options for human fungal infections are available today. In this work, a two-pronged approach was followed: A) Diversification of agriculturally and clinically used antimycotics could contribute to better clinical treatment options. To this end, the new antifungal jagaricin was investigated. As its mode of action, lysis of susceptible biological membranes by formation of large lesions which allow Ca2+ flux was identified. Application of jagaricin is limited to agriculture, as it was found to be toxic for human, but not plant cells. B) A comprehensive understanding of the interactions of human pathogenic fungi with the human immune system can allow the development of targeted treatment strategies. It has been shown before that immune evasion is of great importance in Candida glabrata infection processes. Within the same infection models, C. glabrata exhibited a high affinity to mononuclear cells and has been shown to survive and replicate within their phagosomes. Previous models were not able to reflect long-term persistence of C. glabrata yeasts in macrophages as part of its immune evasion process. Here, this scientific model gap was closed. Most important, C. glabrata was found to be under constant stress in the phagosome within the week-long investigation period. Accordingly, entry into, maintenance of, and exit from cellular quiescence were found to be critical for persistence. Long-term treatment with antimycotics in vitro was not able to fully eradicate C. glabrata yeasts from macrophages, which points to a possible clinical relevance of yeasts which persist in a cellular quiescent state in macrophages. Both approaches have the potential to expand our knowledge on the interactions of fungi with their environment. This knowledge may be used in the future to improve treatment strategies.

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