Phenotype of Mice and Macrophages Deficient in Both Phagocyte Oxidase and Inducible Nitric Oxide Synthase

Abstract

The two genetically established antimicrobial mechanisms of macrophages are production of reactive oxygen intermediates by phagocyte oxidase (phox) and reactive nitrogen intermediates by inducible nitric oxide synthase (NOS2). Mice doubly deficient in both enzymes (gp91(phox-/-)/NOS2(-/-)) formed massive abscesses containing commensal organisms, mostly enteric bacteria, even when reared under specific pathogen-free conditions with antibiotics. Neither parental strain showed such infections. Thus, phox and NOS2 appear to compensate for each other's deficiency in providing resistance to indigenous bacteria, and no other pathway does so fully. Macrophages from gp91(phox-/-)/NOS2(-/-) mice could not kill virulent Listeria. Their killing of S. typhimurium, E. coli, and attenuated Listeria was markedly diminished but demonstrable, establishing the existence of a mechanism of macrophage antibacterial activity independent of phox and NOS2.

Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

“…On the other hand, IL-10 is reported to down-regulate NO production (53). ROS, including free radicals, oxygen ions, and peroxides, have also been implicated in cell damage like NO (56,57). ROS is known to contribute to the efficiency of parasite killing (57,58).…”

“…ROS, including free radicals, oxygen ions, and peroxides, have also been implicated in cell damage like NO (56,57). ROS is known to contribute to the efficiency of parasite killing (57,58). This led to the determination of nitrite and ROS levels in vaccinated vs control mice 8 wk after infection.…”

Genetic regulation of host responses to Salmonella infection in mice

“…Double mutant mice (gp91 phoxÀ/À / Nos2 À/À ) exhibited spontaneous infections caused by organisms of the normal flora, resulting in the formation of large internal abscesses. 125 This phenotype was not exhibited by mice deficient in only one of the enzyme activities, indicating that in spontaneous infections with indigenous flora, gp91 phox and Nos2 can compensate for each other and that no other pathway could compensate for their simultaneous absence.…”

“…Mice deficient in gp91 phox were engineered as a model for CGD and found to be extremely susceptible to infection with Salmonella Typhimurium. 124,125 Early death of gp91 phox -deficient mice after Salmonella infection was associated with spleen and liver bacterial load exceeding by at least 3 log the wild-type controls. 124 Studies with Nos2-deficient mice support a dual role for NO during virulent Salmonella infection in vivo.…”

Mini‐review: Presentation of pathogen‐derived antigens in vivo

“…Although both IFN-+ and TNF- § are required for the early elimination of L. monocytogenes by innate cells [28,29], killing of bacteria also relies on the production of reactive nitrogen intermediates by inducible NO synthase (iNOS) [30]. These iNOS-producing cells were recently identified by Serbina et al [31] as Tip-DC, a subset of CD11c + cells that also secrete TNF- § and that are recruited to the spleen of infected mice through a CCR2-dependent mechanism.…”