Neutrophils are equipped with an array of microbicidal weapons, such as proteases, enzymes that hydrolyze sugars, and proteins that disrupt membranes. This weaponry is stored in at least three different kinds of granules in the cytoplasm. In addition, these cells have a powerful system for generating large amounts of reactive oxygen species. Microorganisms are taken up into an intracellular compartment, called a phagosome, into which these cytotoxic agents are released. It is generally considered that neutrophils use a combination of oxidative and nonoxidative mechanisms to defend against the wide range of microorganisms that they encounter. The microbicidal potential of many of these components is well established (1, 2). However, we really do not know how microbes are killed in the phagosomal environment, where extremely large amounts of oxidants and granule constituents are released and factors such as pH, ionic strength, and enzyme substrate availability are likely to be critical (3). This question is addressed by Tony Segal’s group in their recent Nature paper (4), which elegantly shows how oxidative and nonoxidative mechanisms cooperate. Their findings challenge the established view that direct killing of pathogens by oxidants is the principal arm of neutrophil antimicrobial action.

There is no doubt that the generation of reactive oxygen species is essential for adequate antimicrobial defense. Neutrophils from patients with chronic granulomatous disease (CGD), who are deficient in the NADPH oxidase system responsible for oxidant generation, fail to kill many strains of bacteria, yeasts, and fungi. These same microorganisms also cause the severe infections seen in CGD patients. The NADPH oxidase generates superoxide radical (O2–), the one-electron adduct of molecular oxygen that by itself has limited toxici-