Inducible Defense Mechanism against Nitric Oxide inCandida albicans

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Abstract
The yeastCandida albicansis an opportunistic pathogen that threatens patients with compromised immune systems. Immune cell defenses againstC. albicansare complex but typically involve the production of reactive oxygen species and nitrogen radicals such as nitric oxide (NO) that damage the yeast or inhibit its growth. WhetherCandidadefends itself against NO and the molecules responsible for this defense have yet to be determined. The defense against NO in various bacteria and the yeastSaccharomyces cerevisiaeinvolves an NO-scavenging flavohemoglobin. TheC. albicansgenome contains three genes encoding flavohemoglobin-related proteins,CaYHB1,CaYHB4, andCaYHB5. To assess their roles in NO metabolism, we constructed strains lacking each of these genes and demonstrated that just one,CaYHB1, is responsible for NO consumption and detoxification. InC. albicans, NO metabolic activity andCaYHB1mRNA levels are rapidly induced by NO and NO-generating agents. Loss ofCaYHB1increases the sensitivity ofC. albicansto NO-mediated growth inhibition. In mice, infections withCandidastrains lackingCaYHB1still resulted in lethality, but virulence was decreased compared to that in wild-type strains. Thus,C. albicanspossesses a rapid, specific, and highly inducible NO defense mechanism involving one of three putative flavohemoglobin genes.