Phagocyte NADPH oxidase, but not inducible nitric oxide synthase is essential for early control of Burkholderia cepacia and Chromobacterium violaceum infection in mice

Reactive oxygen and nitrogen intermediates have critical, partially overlapping roles in host defense against a variety of pathogens. Using mice deficient in generating phagocyte superoxide (p47(phox-/-)) and mice deficient in generating inducible nitric oxide synthase (iNOS(-/-)), we examined the roles of these reactive species in host defense against Burkholderia cepacia and Chromobacterium violaceum, organisms known to have unusual virulence in chronic granulomatous disease. Intraperitoneal B. cepacia challenge (4.0 X 10(3) to 4.0 X 10(5) organisms/mouse) resulted in mortality in all p47(phox-/-) mice, with the survival interval being inversely proportionate to the amount of inoculum. Pretreatment with gamma interferon did not affect survival. C. violaceum was strikingly virulent in p47(phox-/-) mice (the 50% lethal dose [LD50] was < 13 organisms). iNOS(-/-)and wild-type mice were resistant to B. cepacia challenges of at least 106 organisms per mouse, and the LD50 of C. violaceum was between 10(6) and 10(7) organisms per mouse. Consistent with the survival data, numbers of organisms in cultures of B. cepacia from multiple sites were higher for p47(phox-/-) mice than for iNOS(-/-) and wild-type mice at day 4 after challenge, but numbers of organisms for different B. cepacia strains varied. The recovery of C. violaceum was strikingly greater at 18 h after challenge for p47(phox-/-) mice than for iNOS(-/-) and wild-type mice, in which the organism burdens were virtually nil. In vitro, both B. cepacia and C. violaceum were sensitive to H2O2 and to reactive nitrogen intermediates but the sensitivities of different strains varied significantly. Host defense against B. cepacia and C violaceum is critically dependent in vivo on reactive oxygen intermediates, and these species are model organisms to further dissect host and pathogen interactions related to the generation and scavenging of microbicidal reactive intermediates.