mBio (Dec 2023)
Candida albicans resistance to hypochlorous acid
Abstract
ABSTRACTInnate immune cells, especially neutrophils, play key roles in protecting against infection by Candida albicans and other fungal pathogens. A distinct aspect of neutrophils compared to other phagocytes is that they make much higher levels of myeloperoxidase, which converts H2O2 generated during the oxidative burst into highly reactive hypochlorous acid (HOCl). The effects of HOCl on C. albicans are not well defined, so comparative studies were used to show that HOCl kills C. albicans at lower doses than H2O2 and in a manner that correlates with permeabilization of the plasma membrane. Mutants with defects in plasma membrane organization and antioxidant pathways showed differential sensitivity to these oxidants, consistent with their distinct chemical properties. Transcriptional responses to HOCl and H2O2 were also quite different. Although they induced a common set of genes, most differentially regulated genes were unique. Testing the roles of genes that were predicted to be important for counteracting the types of thiol oxidation that are preferentially caused by HOCl showed that Mxr1 (methionine-S-sulfoxide reductase), Srx1 (sulfiredoxin that reduces cysteine-sulfinic acid groups), and Trx1 (thioredoxin that acts to reduce disulfide bonds) all promoted resistance to HOCl. Altogether, these results suggest that an effective way to help promote the killing of C. albicans by neutrophils would be to perturb the C. albicans plasma membrane, rather than targeting one specific antioxidant pathway.IMPORTANCEHypochlorous acid (HOCl), commonly known as bleach, is generated during the respiratory burst by phagocytes and is a key weapon used to attack Candida albicans and other microbial pathogens. However, the effects of hypochlorous acid on C. albicans have been less well studied than H2O2, a different type of oxidant produced by phagocytes. HOCl kills C. albicans more effectively than H2O2 and results in disruption of the plasma membrane. HOCl induced a very different transcriptional response than H2O2, and there were significant differences in the susceptibility of mutant strains of C. albicans to these oxidants. Altogether, these results indicate that HOCl has distinct effects on cells that could be targeted in novel therapeutic strategies to enhance the killing of C. albicans and other pathogens.
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