Editorial: Of Mice and Men—Yet Again

Candida albicans infections at skin and mucosal sites are common, but organisms hardly ever invade deeper tissues. Candida species, with albicans the most common, are typically low-abundance commensals among skin, gastrointestinal, and vaginal flora. Conditions that permit Candida overgrowth often provoke surrounding tissues to warmth, redness, itching or pain, and discharge—an inflammatory response. Facilitating factors for these conditions, known as mucocutaneous candidiasis, include persistent moisture; administration of antibacterial antibiotics that reduce competing flora without suppressing candidal growth; high levels of glucose in mucosal secretions, as would be expected in poorly controlled diabetics; or subtle defects in immunity, particularly in IL-17-mediated pathways [1]. Blood and deeper tissue infections with Candida species, once rarely encountered, are now more common. Contributing factors include medical practices of (1) prolonged systemic administration of antibacterials that have no direct effect on fungi, (2) long-term use of i.v. catheters, and (3) persistent neutropenia, usually consequent to cancer therapies. New insights regarding barriers to Candida invasiveness emerged with the evaluation, in 1968, of a 49-year-old diabetic who had had two or three deepseated Candida infections in the previous 4 years but with none of the risk factors described above [2]. This individual proved to have a genetic, complete absence of MPO, a phagocyte enzyme that catalyzes the oxidation of chloride by H2O2 to hypochlorous acid, a potent microbicide. Typically, MPO is packaged in phagocyte (neutrophil and monocyte) cytoplasmic granules that merge with the developing phagocytic compartment. Concurrently, a membrane oxidase is activated to reduce dissolved molecular oxygen, first to superoxide anion and then to H2O2 (the respiratory burst). Together with chloride from the ambient medium, all components of a potent, intravacuolar, antimicrobial system are assembled and active within the confined space of the phagocytic vacuole. This MPO-mediated microbicidal system overlaps with many other intravacuolar antimicrobial systems, and it is often difficult to establish a hierarchy of importance for each system’s contribution (for a recent review, see ref. [3]). For C. albicans, however, the MPO-deficient neutrophils from this patient were shown to be impaired extensively in their ability to kill ingested yeasts (Fig. 1). Furthermore, they were severely impaired in their capacity to suppress filamentation (Fig. 2). C. albicans is a dimorphic fungus, encountered environmentally as a yeast–an oval spheroid–that replicates by budding off daughter yeasts. Under different environmental conditions, notably a temperature shift to 37°C and exposure to host tissue factors, yeasts begin to extend long filaments in a process known as germ-tube formation, germination, or filamentation. Filaments can become the dominant morphology, growing to become complex, intertwined mats. This latter morphology is associated with invasive behavior. Normal human neutrophils not only kill a large proportion of ingested C. albicans, but they also suppress filamentation in the remainder. Optimal suppression requires the oxygen-derived products of the respiratory burst and MPO, with the absence of the former leading to a more severe defect than just the absence of MPO (Fig. 2). When the influx of neutrophils is limited, as in the conduct of a typical in vitro experiment, suppression of filamentation, even by normal neutrophils, is limited in duration. Filaments from surviving fungi may ultimately grow beyond the capacity of the phagocyte to contain them, leading to rupture of the host cell and dissemination of the microbe. Of note, the proband patient for MPO deficiency did not have a major infection history until age 45, concurrent with the clinical recognition of his diabetes, even though he was, presumably, completely MPO deficient from birth. Also, the proband’s sister, with identical MPO deficiency but not diabetes, had no unusual infection history. As additional individuals with complete hereditary MPO deficiency were identified, it became clear that most do not exhibit an unusual susceptibility to bacterial or fungal infections, at least in the setting of modern sanitation practices and health-care interventions. When they do, infections seem to emerge in the setting of diabetes, and C. albicans is, by far, the most prominent, unusual pathogen. Absence of the capacity to generate a phagocyte respiratory burst, which impairs more than just the MPO system, as in CGD, brings overall infection risk to a new, life-threatening level. Still, bacterial infections are more common than fungal, and even within the fungal group, serious aspergillus infections seem to be more prominent than candida, suggesting that even with severely impaired neutrophils, CGD patients retain significant anticandidal defenses overall.