Reactive oxygen species delay control of lymphocytic choriomeningitis virus

• Published in: Cell death and differentiation Vol. 20; no. 4; pp. 649 - 658
• Main Authors: Lang, P A, Xu, H C, Grusdat, M, McIlwain, D R, Pandyra, A A, Harris, I S, Shaabani, N, Honke, N, Kumar Maney, S, Lang, E, Pozdeev, V I, Recher, M, Odermatt, B, Brenner, D, Häussinger, D, Ohashi, P S, Hengartner, H, Zinkernagel, R M, Mak, T W, Lang, K S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2013; Nature Publishing Group
• Subjects: 631/250/1933; 631/80/86; 692/699/255/2514; 692/700/139/422; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Breast cancer; Buthionine Sulfoximine - pharmacology; Cancer research; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Biology; Cell Cycle Analysis; Cell death; Cell Survival; Cells, Cultured; Chronic infection; Differentiation; Disease Models, Animal; Glutathione - metabolism; Granulocytes; Health care networks; Hepatitis C; Hepatocytes; Hospitals; Immune response; Immunology; Infections; Leukocytes (granulocytic); Life Sciences; Liver; Liver - metabolism; Lymphocytes; Lymphocytes T; Lymphocytic Choriomeningitis - pathology; Lymphocytic Choriomeningitis - prevention & control; Lymphocytic Choriomeningitis - virology; Lymphocytic choriomeningitis virus; Lymphocytic choriomeningitis virus - drug effects; Lymphocytic choriomeningitis virus - physiology; Macrophages; Medical research; Mice; Mice, Inbred C57BL; Mice, Knockout; NAD(P)H oxidase; NADPH; NADPH Oxidases - deficiency; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Neutrophils; Original Paper; Protons; Reactive oxygen species; Reactive Oxygen Species - metabolism; Regulatory subunits; Rheumatoid arthritis; Ribonucleic acid; RNA; Spleen; Spleen - metabolism; Stem Cells; Tumor necrosis factor-TNF; Viral infections; Canada; Germany; hepatitis; virus; liver cell damage; ROS
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2012.167

Cluster of differentiation (CD)8 + T cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T-cell-mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus-infected liver and spleen tissues that were triggered by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8 + T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T-cell function was elevated in p47phox-deficient ( Ncf1 −/− ) mice. In the absence of p47phox, enhanced T-cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage.