You are here
Defective localization of the NADPH phagocyte oxidase to Salmonella-containing phagosomes in tumor necrosis factor p55 receptor-deficient macrophages.
Title | Defective localization of the NADPH phagocyte oxidase to Salmonella-containing phagosomes in tumor necrosis factor p55 receptor-deficient macrophages. |
Publication Type | Journal Article |
Year of Publication | 2001 |
Authors | Vazquez-Torres, A, Fantuzzi, G, Edwards, CK, Dinarello, CA, Fang, FC |
Journal | Proc Natl Acad Sci U S A |
Volume | 98 |
Issue | 5 |
Pagination | 2561-5 |
Date Published | 2001 Feb 27 |
ISSN | 0027-8424 |
Keywords | Animals, Antigens, CD, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Fluorescence, NADPH Oxidase, Phagosomes, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Salmonella |
Abstract | Tumor necrosis factor receptor (TNFR) p55-knockout (KO) mice are susceptible 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 nitrogen species in response to Salmonella but nevertheless exhibit poor bactericidal activity. Treatment with IFN-gamma enhances killing by wild-type macrophages but does not restore the killing defect of TNFR-KO cells. Bactericidal activity of macrophages can be abrogated by a deletion in the gene encoding TNFalpha but not by saturating concentrations of TNF-soluble receptor, suggesting that intracellular TNFalpha 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 bacterial strain lacking the type III secretory system encoded by Salmonella pathogenicity island 2 (SPI2), suggesting that TNFalpha and SPI2 have opposing actions on a common pathway of vesicular trafficking. TNFalpha-TNFRp55 signaling plays a critical role in the immediate innate immune response to an intracellular pathogen by optimizing the delivery of toxic reactive oxygen species to the phagosome. |
DOI | 10.1073/pnas.041618998 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 11226278 |
PubMed Central ID | PMC30177 |
Grant List | AI15614 / AI / NIAID NIH HHS / United States AI39557 / AI / NIAID NIH HHS / United States AI44486 / AI / NIAID NIH HHS / United States |