Acetic acid bacteria were previously considered nonpathogenic in humans. However, over the past decade, five genera of Acetobacteraceae have been isolated from patients with inborn or iatrogenic immunodeficiencies. Here, we describe the first studies of the interactions of the human innate immune system with a member of this bacterial family, Granulibacter bethesdensis, an emerging pathogen in patients with chronic granulomatous disease (CGD). Efficient phagocytosis of G. bethesdensis by normal and CGD polymorphonuclear leukocytes (CGD PMN) required heat-labile serum components (e.g., C3), and binding of C3 and C9 to G. bethesdensis was detected by immunoblotting. However, this organism survived in human serum concentrations of >90%, indicating a high degree of serum resistance. Consistent with the clinical host tropism of G. bethesdensis, CGD PMN were unable to kill this organism, while normal PMN, in the presence of serum, reduced the number of CFU by about 50% after a 24-h coculture. This finding, together with the observations that G. bethesdensis was sensitive to H 2 O 2 but resistant to LL-37, a human cationic antimicrobial peptide, suggests an inherent resistance to O 2 -independent killing. Interestingly, 10 to 100 times greater numbers of G. bethesdensis were required to achieve the same level of reactive oxygen species (ROS) production induced by Escherichia coli in normal PMN. In addition to the relative inability of the organism to elicit production of PMN ROS, G. bethesdensis inhibited both constitutive and FASinduced PMN apoptosis. These properties of reduced PMN activation and resistance to nonoxidative killing mechanisms likely play an important role in G. bethesdensis pathogenesis.
Granulibacter bethesdensis is a Gram-negative pathogen first isolated from a patient with chronic granulomatous disease (CGD) in 2003 (13). G. bethesdensis has since been cultured from at least 5 patients with CGD in the United States (15, 16) and 1 in Spain (23), justifying its classification as an emerging pathogen in this primary immunodeficiency. Although the bacterial family to which G. bethesdensis belongs-the Acetobacteraceae-was previously considered nonpathogenic in humans, case reports of human infections by other members of this family are being published with increasing frequency (1,2,5,6,9,12,17,22,26,27). Common elements of infection by these other Acetobacteraceae species appear to include intravenous drug administration (for either medicinal or recreational purposes), organ transplant, or chronic medical problems requiring dialysis. In contrast, G. bethesdensis has been reported only in patients with CGD, a disease resulting from inadequate superoxide anion production required for normal myeloid host defenses. While G. bethesdensis is the only member of this family for which Koch's postulates have been fulfilled (13), there is scant information about the mechanisms of pathogenesis of infection by these organisms. Although mice with CGD are significantly more susceptible than normal mice to infection by...