Lessons about the pathogenesis and management of aspergillosis from studies in chronic granulomatous disease.

Chronic Granulomatous Disease (CGD) is a rare disorder caused by mutations in the NADPH oxidase. The CGD phenotype includes granuloma formation and susceptibility to infection with microorganisms including Aspergillus. The immune adjuvant interferon-gamma and the antifungal agent itraconazole have reduced the incidence of infections in CGD. Studies using CGD phagocytes have shown that reactive oxygen species (ROS), products of the NAPDH oxidase, are critical for killing Aspergillus hyphae. But despite lack of ROS production, CGD patients generally only get infected with Aspergillus after heavy exposure. To study why CGD patients are not infected with Aspergillus more frequently we studied host defense against this ubiquitous mold further. We found that neutrophil lactoferrin is fungistatic for Aspergillus fumigatus spores by chelation of iron, an essential growth factor. Thus, the neutrophil employs both nonoxidative (lactoferrin) and oxidative (hydrogen peroxide) defense mechanisms against A. fumigatus spores and hyphae, respectively.