Necrosis in Chronic Granulomatous Disease Induces Neutrophil Burkholderia cenocepacia

Burkholderia cepacia complex is a life-threatening group of pathogens for patients with chronic granulomatous disease (CGD), whose phagocytes are unable to produce reactive oxygen species (ROS). Unlike other CGD pathogens, B. cepacia complex is particularly virulent, characteristically causing septicemia, and is the bacterial species responsible for most fatalities in these patients. We found that a nonmucoid Burkholderia cenocepacia (a predominant species in the B. cepacia complex) isolate was readily ingested by normal human neutrophils under nonopsonic conditions and promoted apoptosis in these cells. The proapop-totic effect was not due to secreted bacterial products, but was dependent on bacterial viability. Phagocytosis was associated with a robust production of ROS, and the apoptotic neutrophils could be effectively cleared by monocyte-derived macrophages. The proapoptotic effect of B. cenocepacia was independent of ROS production because neutrophils from CGD patients were rendered apoptotic to a similar degree as control cells after challenge. More importantly, neutrophils from CGD patients, but not from normal individuals, were rendered necrotic after phagocytosis of B. cenocepacia. The extreme virulence of B. cepacia complex bacteria in CGD, but not in immunocompetent hosts, could be due to its necrotic potential in the absence of ROS. C hronic granulomatous disease (CGD) 3 is a rare primary immunodeficiency resulting from genetic defects in components of the phagocyte NADPH-oxidase, rendering the patient's phagocytes unable to produce the reactive oxygen species (ROS) needed for proper antimicrobial activity (1). These patients suffer from recurrent infections with a distinct set of fungal and bacterial species and often display various inflammatory complications , including granuloma formation (2). The leading bacterial cause of CGD fatalities are members of the Burkholderia cepacia complex, a complex that includes nine distinct species (3). Burk-holderia cenocepacia (formerly known as genomovar III) is a particularly problematic pathogen in patients with cystic fibrosis (CF) (4), but no particular species from the complex appears to predominate in CGD. B. cepacia complex bacteria possess intrinsic resistance to many antibiotics and can be transmitted from patient to patient in CF, making infection with these bacteria a particularly difficult clinical challenge. B. cepacia complex bacteria are highly resistant to cationic antibacterial peptides (5), crucial components of the oxygen-independent killing machinery of phagocytes, rendering these pathogens especially well suited for infection in CGD. Their particular virulence in patients with CF has not been elucidated. B. cepacia complex infections in CGD patients are often remarkably aggressive, and the majority of the fatalities …