Leukocyte myeloperoxidase deficiency and disseminated candidiasis: the role of myeloperoxidase in resistance to Candida infection

Abstract

A B S T R A C T The neutrophils and monocytes of a patient with disseminated candidiasis were found to lack detectable levels of the lysosomal enzyme myeloperoxidase (MPO), although they had normal levels of other granule-associated enzymes. Leukocytes from one of the patient's sisters also lacked detectable MPO; leukocytes from his four sons contained approximately one-third of mean normal peroxidase levels. Neither the patient nor his affected relatives had experienced frequent or unusual bacterial infections.The phagocytic activity of the patient's MPO-deficient neutrophils was intact, and the cells displayed normal morphologic and metabolic responses to phagocytosis. In contrast to normal leukocytes which killed 30.5 ±7.3% of ingested Candida albicans in 1 hr, however, the patient's neutrophils killed virtually none. His leukocytes also failed to kill the strain of C. albicans recovered from his lesions, as well as other Candida. species. These MPO-deficient neutrophils killed Serratia marcescens and Staphylococcus aureus 502A at an abnormally slow rate, requiring 3-4 hr to achieve the bactericidal effect attained by normal leukocytes after 45 min. No other abnormalities in his cellular or humoral immune responses were demonstrated.These findings suggest that hereditary MPO deficiency is transmitted as an autosomal recessive characteristic, that the homozygous state conveys enhanced susceptibility to disseminated candidiasis, and that MPO is necessary for candidacidal activity in human neutrophils.This work was presented in part at the National Meeting of the American Federation for Clinical Research, Atlantic City, N. J., and published in abstract form (1).

Mechanisms of Attachment of Neutrophils to Candida albicans Pseudohyphae in the Absence of Serum, and of Subsequent Damage to Pseudohyphae by Microbicidal Processes of Neutrophils In Vitro

“…The inhibitory effects of azide and cyanide suggest a role for myeloperoxidase (47), though these compounds may have some inhibitory effects on cell respiration as well. It is known that myeloperoxidase, hydrogen peroxide, and iodide can kill Candida albicans yeasts (13), and that myeloperoxidase-deficient neutrophils cannot kill Candida albicans yeasts normally (14). A role for hydrogen peroxide in damage to pseudohyphae is supported by inhibition by catalase, as well as the defect in damage to pseudohyphae by neutrophils from a patient with chronic granulomatous disease.…”

“…Yeast forms of Candida are killed by oxidative mechanisms of neutrophils (11)(12)(13)(14). Our earlier studies indicated that Candida pseudohyphae were iodinated by neutrophils (1), suggesting that incomplete ingestion of pseudohyphae activates oxidative microbicidal mechanisms in the neutrophil (14)(15)(16). In some circumstances, other mechanisms of candidacidal activity may be involved (18), including granulocyte cationic proteins (19).…”

Antibacterial activity of cationic proteins from human granulocytes.

“…Streptococci (4), Lactobacilli (5), and Pneumococci (6), are readily killed even in CGD granulocytes. Furthermore, individuals deficient in myeloperoxidase usually do not have excessive infections, and their granulocytes kill ingested bacteria, although at a reduced rate (7,8). Therefore, alternative microbicidal mechanisms might exist that do not involve the myeloperoxidase-hydrogen peroxide system.…”

Genetic analysis of innate immunity in resistance to Candida albicans

“…They are rapidly recruited to the sites of infection. Among the mechanisms employed by neutrophils to control infection are: phagocytosis of C. albicans, 39,40 production of reactive oxygen species, 41 and the release of mediators, including cytokines and antimicrobial substances. 42 In animals that are pretreated with agents to reduce the number of neutrophils, there is a significantly increased susceptibility to systemic C. albicans challenge.…”

“…86 Defects in these complexes have been implicated in enhanced susceptibility to candidiasis. 24,41 NADPH oxidase generates superoxide anion during the phagocytosis-associated respiratory burst. Mice with X-linked chronic granulomatous disease (X-CGD), which have deficiencies in NADPH oxidase, have an increased susceptibility to disseminated candidiasis, as determined by survival time and fungal load.…”