Defective localization of the NADPH phagocyte oxidase to Salmonella-containing phagosomes in tumor necrosis factor p55 receptor-deficient macrophages

Tumor necrosis factor receptor (TNFR) p55-knockout (KO) mice are susceptibl e profoundly to Salmonella infection. One day after peritoneal inoculation, TNFR-KO mice harbor 1,000-fold more bacteria in liver and spleen than wild -type mice despite the formation of well organized granulomas. Macrophages from TNFR-KO mice produce abundant quantities of reactive oxygen and nitrog en species in response to Salmonella but nevertheless exhibit poor bacteric idal activity. Treatment with IFN-gamma enhances killing by wild-type macro phages but does not restore the killing defect of TNFR-KO cells. Bactericid al activity of macrophages can be abrogated by a deletion in the gene encod ing TNF alpha but not by saturating concentrations of TNF-soluble receptor, suggesting that intracellular TNF alpha can regulate killing of Salmonella by macrophages. Peritoneal macrophages from TNFR-KO mice fail to localize NADPH oxidase-containing vesicles to Salmonella-containing vacuoles. A TNFR -KO mutation substantially restores virulence to an attenuated mutant bacte rial strain lacking the type III secretory system encoded by Salmonella pat hogenicity island 2 (SPI2), suggesting that TNF alpha and SPI2 have opposin g actions on a common pathway of vesicular trafficking. TNF alpha -TNFRp55 signaling plays a critical role in the immediate innate immune response to an intracellular pathogen by optimizing the delivery of toxic reactive oxyg en species to the phagosome.