Abstract
Systemic infections of humans with the fungal pathogen Candida albicans are associated with a high mortality rate. Currently, efficient treatment of these infections is hampered by the relatively low number of available antifungal drugs. We recently identified the small heat shock protein Hsp21 in C. albicans and demonstrated its fundamental role for environmental stress adaptation and fungal virulence. Hsp21 was found in several pathogenic Candida species but not in humans. This prompted us to investigate the effects of a broad range of different antifungal drugs on an Hsp21-null C. albicans mutant strain. Our results indicate that combinatorial therapy targeting Hsp21, together with specific antifungal drug targets, has strong synergistic potential. In addition, we demonstrate that Hsp21 is required for tolerance to ethanol-induced stress and induction of filamentation in response to pharmacological inhibition of Hsp90. These findings might pave the way for the development of new treatment strategies against Candida infections.
Highlights
Candida albicans is one of the major fungal pathogens of humans and can cause life-threatening systemic infections with mortality rates approaching 50% [1]
Heat shock proteins (Hsps) are divided into five classes - Hsp100, Hsp90, Hsp70, Hsp60 and the small heat shock proteins depending on their molecular mass [10,11]
Compromising Hsp90 leads to reduced biofilm formation [17], increased sensitivity to antifungal drugs [14,16], and attenuated virulence of C. albicans in a mouse model of hematogenously disseminated candidasis [14,18,19]
Summary
Candida albicans is one of the major fungal pathogens of humans and can cause life-threatening systemic infections with mortality rates approaching 50% [1]. Treatment of such infections is complicated due to the restricted number of efficient antifungal drugs, antifungal drug toxicity, and insufficient diagnostic tools [2,3]. Heat shock proteins (Hsps) are found in virtually all living organisms, including humans and fungi. They fulfill a plethora of cellular functions, including folding, unfolding or refolding of other proteins (clients), translocation of client proteins across membranes, activation of clients, and prevention of uncontrolled protein aggregation [7]. Hsps are divided into five classes - Hsp100, Hsp, Hsp, Hsp and the small heat shock proteins (sHsps) depending on their molecular mass [10,11]
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