title: Increased mortality and dysregulated cytokine production in tumor necrosis factor receptor 1-deficient mice following systemic Klebsiella pneumoniae infection.
abstract: A significant clinical complication of pulmonary infections with Klebsiella pneumoniae is peripheral blood dissemination, resulting in a systemic infection concurrent with the localized pulmonary infection. In this context, little is known about the role of tumor necrosis factor receptor 1 (TNFR1)-mediated innate immune responses during systemic Klebsiella infections. Mice lacking TNFR1 were significantly more susceptible to Klebsiella-induced mortality following intravenous inoculation. Bacterial clearance was impaired in TNFR1-deficient mice at early times following infection. Unexpectedly, bacterial burdens at the onset of mortality (days 2 to 3 postinfection) were not higher in mice lacking TNFR1. However, elevated production of liver-associated proinflammatory cytokines (interleukin-12, tumor necrosis factor alpha [TNF-alpha[, and gamma interferon [IFN-gamma]) and chemokines (MIP-1 alpha, MIP-2, and MCP-1) was observed within the first 24 h of infection. Additionally, excessive plasma-associated IFN-gamma was also observed late in the course of infection (day 3). Spleen cells from day-3 infected TNFR1-deficient mice secreted markedly enhanced levels of IFN-gamma when cultured in vitro. Additionally, there was a marked increase in the total number of activated lymphocyte subsets as indicated by CD69 upregulation. A notable exception was the sharp decrease in the frequency of splenic NK T cells in infected TNFR1 knockout (KO) mice. Anti-TNF-alpha therapy in TNFR1 KO mice significantly reduced chemokine production and liver injury. Combined, these data indicate a dysregulated antibacterial host response following intravenous Klebsiella infection in the absence of TNFR1 signaling, resulting in heightened cytokine production and hyperactivation of specific splenic lymphocyte subsets.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0642, USA. tmoore@umich.edu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Moore
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Perry
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Getsoian
authors.forename: Christine L
authors.initials: CL
authors.lastname: Monteleon
authors.forename: Anna L
authors.initials: AL
authors.lastname: Cogen
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D007710:Klebsiella Infections / Q000276:immunology*; D007711:Klebsiella pneumoniae; D008099:Liver / Q000276:immunology / Q000293:injuries; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009500:Neutralization Tests; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D015703:Antigens, CD; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma