Inhibition of ROS and upregulation of inflammatory cytokines by FoxO3a promotes survival against Salmonella typhimurium.
Virulent intracellular pathogens, such as the Salmonella species, engage numerous virulence factors to subvert host defence mechanisms to induce a chronic infection that leads to typhoid or exacerbation of other chronic inflammatory conditions. Here we show the role of the forkhead transcription factor FoxO3a during infection of mice with Salmonella typhimurium (ST). Although FoxO3a signalling does not affect the development of CD8(+) T cell responses to ST, FoxO3a has an important protective role, particularly during the chronic stage of infection, by limiting the persistence of oxidative stress. Furthermore, FoxO3a signalling regulates ERK signalling in macrophages, which results in the maintenance of a proinflammatory state. FoxO3a signalling does not affect cell proliferation or cell death. Thus, these results reveal mechanisms by which FoxO3a promotes host survival during infection with chronic, virulent intracellular bacteria.
Faculty of Medicine, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H8M5.
Julie
J
Joseph
Faculty of Medicine, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H8M5.
Emmanuelle S
ES
Ametepe
Faculty of Medicine, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H8M5.
Naveen
N
Haribabu
Faculty of Medicine, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H8M5.|National Research Council of Canada-Human Health Therapeutics, Ottawa, Ontario, Canada K1A0R6.
Gerard
G
Agbayani
Faculty of Medicine, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H8M5.|National Research Council of Canada-Human Health Therapeutics, Ottawa, Ontario, Canada K1A0R6.
Lakshmi
L
Krishnan
Faculty of Medicine, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H8M5.
Alexandre
A
Blais
Faculty of Medicine, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H8M5.
Subash
S
Sad
D000818:Animals; D018414:CD8-Positive T-Lymphocytes; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D012333:RNA, Messenger; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors*; D012481:Salmonella Infections, Animal / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000472:pathogenicity*; D015398:Signal Transduction
D016207:Cytokines; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species