Anti-Tumor Necrosis Factor-?? Therapy During Murine Klebsiella pneumoniae Bacteremia: Increased Mortality in the Absence of Liver Injury

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Abstract
Klebsiella pneumoniae is a leading cause of gram-negative bacterial pneumonia, often resulting in bacteremia concurrent with the localized pulmonary infection. The beneficial role of tumor necrosis factor (TNF)-α during pulmonary infection has been well documented; however, consequences of TNF-α production during systemic bacterial infection are controversial. A murine model of K. pneumoniae was developed to address this important issue. Liver-associated TNF-α mRNA was induced within 30 min after intravenous bacterial inoculation and remained elevated through 6 h before returning to near-baseline at 24 h postinfection. Intravenous K. pneumoniae infection induced liver cellular injury that was completely ablated when mice were pretreated with a neutralizing anti-TNF-α antibody. Interestingly, this reduction in liver injury failed to translate into improved survival. Mice receiving anti-TNF-α continued to succumb to the infection even out to day 10 postinfection. Bacterial clearance after TNF-α neutralization was significantly impaired at later time points during infection. Correlating with impaired bacterial clearance was diminished production of liver-associated MIP-2, MIP-1α, MCP-1, and interferon-γ. Further evidence of diminished antibacterial immune responses was noted when the activational status of splenic natural killer cells in anti-TNF-α-treated mice was examined 24 h postinfection. Natural killer cells displayed decreased CD69 expression. Combined, these data indicate that the beneficial effects of TNF-α during systemic K. pneumoniae infection outweigh the detrimental effects of TNF-α-mediated hepatocyte cellular injury. Anti-TNF-α therapy, although preventing liver injury during blood-borne bacterial infection, results in a dampened anti-bacterial host response, resulting in decreased bacterial clearance and overall survival.

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