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Infection and Immunity, September 2003, p. 4891-4900, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.4891-4900.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Increased Mortality and Dysregulated Cytokine Production in Tumor Necrosis Factor Receptor 1-Deficient Mice following Systemic Klebsiella pneumoniae Infection

Thomas A. Moore,* Michelle L. Perry, Andrew G. Getsoian, Christine L. Monteleon, Anna L. Cogen, and Theodore J. Standiford

Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan

Received 24 February 2003/ Returned for modification 17 April 2003/ Accepted 27 May 2003

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.

* Corresponding author. Mailing address: University of Michigan Medical Center, Division of Pulmonary and Critical Care Medicine, 6301 MSRB III, 1150 West Medical Center Dr., Ann Arbor, MI 48109-0642. Phone: (734) 647-8378. Fax: (734) 764-4556. E-mail: tmoore{at}umich.edu.

Editor: J. N. Weiser

Infection and Immunity, September 2003, p. 4891-4900, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.4891-4900.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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