Increased mortality and dysregulated cytokine production in tumor necrosis factor receptor 1-deficient mice following systemic Klebsiella pneumoniae infection


Moore, TA; Perry, ML; Getsoian, AG; Monteleon, CL; Cogen, AL; Standiford, TJ; (2003) Increased mortality and dysregulated cytokine production in tumor necrosis factor receptor 1-deficient mice following systemic Klebsiella pneumoniae infection. Infection and immunity, 71 (9). pp. 4891-900. ISSN 0019-9567 DOI: https://doi.org/10.1128/IAI.71.9.4891-4900.2003

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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.

Item Type: Article
Keywords: Animals, Antigens, CD/genetics/physiology, Chemokines/biosynthesis, Cytokines/*biosynthesis, Inflammation Mediators/metabolism, Interferon-gamma/biosynthesis, Klebsiella Infections/*immunology, *Klebsiella pneumoniae, Liver/immunology/injuries, Lymphocyte Activation, Lymphocyte Subsets/immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutralization Tests, Receptors, Tumor Necrosis Factor/*deficiency/genetics/physiology, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Tumor Necrosis Factor-alpha/antagonists & inhibitors, Animals, Antigens, CD, genetics, physiology, Chemokines, biosynthesis, Cytokines, biosynthesis, Inflammation Mediators, metabolism, Interferon-gamma, biosynthesis, Klebsiella Infections, immunology, Klebsiella pneumoniae, Liver, immunology, injuries, Lymphocyte Activation, Lymphocyte Subsets, immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutralization Tests, Receptors, Tumor Necrosis Factor, deficiency, genetics, physiology, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Tumor Necrosis Factor-alpha, antagonists & inhibitors
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Clinical Research
PubMed ID: 12933830
Web of Science ID: 184996600009
URI: http://researchonline.lshtm.ac.uk/id/eprint/1757

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