Functional Aspects of a Second Mechanism of Candidacidal Activity by Human Neutrophils

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Abstract
We tested the ability of human neutrophils to kill five Candida species and the yeast Torulopsis glabrata. C. parapsilosis and C. pseudotropicalis were found to be killed readily by normal and myeloperoxidase-deficient neutrophils and were selected to probe the myeloperoxidase-independent fungicidal mechanisms of the neutrophil. These organisms were killed with relatively normal (C. parapsilosis) or moderately reduced (C. pseudotropicalis) effectiveness by neutrophils from two boys with X-linked chronic granulomatous disease. Azide (2 mm) and sulfadiazine (4 mm) exerted a relatively small inhibitory effect on the ability of normal neutrophils to kill C. parapsilosis. These compounds did not, however, inhibit the killing of C. parapsilosis by myeloperoxidase-deficient neutrophils, although they blocked their iodination of ingested Candida cells. Anaerobic incubation conditions inhibited the ability of normal neutrophils to kill C. parapsilosis slightly but did not impair this function in myeloperoxidase-deficient cells. All of the Candida species tested had catalase activity, yet their sensitivity to H2O2 in cell-free systems varied considerably. Our C. parapsilosis strain was extraordinarily resistant to H2O2 (LD75: 0.14 m), as compared with C. pseudotropicalis or with our reference strain of C. albicans (LD75: 2.3 × 10−3m and 3.4 × 10−3m, respectively). These data establish the existence in human neutrophils of a second mechanism that exerts microbicidal activity against certain Candida species; the mechanism is unrelated to myeloperoxidase, iodination, or to the direct effects of H2O2 generated by the endogenous metabolic processes of the neutrophil. As yet unidentified, this mechanism appears to remain operative in the neutrophils of subjects with hereditary myeloperoxidase deficiency or chronic granulomatous disease.