Mammalian heme oxygenases play important roles in immune regulation by producing immunosuppressive CO. The pathogenic yeast C. albicans encodes a heme oxygenase, Hmx1, that is specifically induced by the host protein hemoglobin, suggesting a role in the pathogenesis of disseminated bloodstream infections. We show that exposing mice to therapeutic levels of CO increases C. albicans virulence, whereas a HMX1 null strain has decreased virulence in murine disseminated candidiasis. Levels of several regulatory cytokines and chemokines are decreased in mice infected with the null strain, and initial lesions in the kidney are more rapidly cleared following PMN infiltration. Reconstitution of one or both alleles restores virulence to the level of wild type. Growth in vitro and initial organ burdens in infected mice are not decreased and host iron overload does not restore virulence for the null strain, suggesting that early growth in the host is not limited by Hmx1-mediated iron scavenging. In contrast, inhaled CO partially reverses the virulence defect of the null strain and restores several host cytokine responses to wild type levels. Collectively, these results show that C. albicans Hmx1 expression and CO production limit the host immune response and contribute to the pathogenesis of candidemia. The higher fungi exhibit a dichotomy with regard to urea utilization. The hemiascomycetes use urea amidolyase (DUR1,2), whereas all other higher fungi use the nickel-containing urease. Urea amidolyase is an energy-dependent biotin-containing enzyme. It likely arose before the Euascomycete/Hemiascomycete divergence c. 350 million years ago by insertion of an unknown gene into one copy of a duplicated methylcrotonyl CoA carboxylase (MccA). The dichotomy between urease and urea amidolyase coincides precisely with that for the Ni/Co transporter (Nic1p), which is present in the higher fungi that use urease and is absent in those that do not. We suggest that the selective advantage for urea amidolyase is that it allowed the hemiascomycetes to jettison all Ni(2+)- and Co(2+)-dependent metabolisms and thus to have two fewer transition metals whose concentrations need to be regulated. Also, the absence of MccA in the hemiascomycetes coincides with and may explain their production of fusel alcohols.
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