Anti-tumor necrosis factor-alpha therapy during murine Klebsiella pneumoniae bacteremia: increased mortality in the absence of liver injury.
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)-alpha during pulmonary infection has been well documented; however, consequences of TNF-alpha production during systemic bacterial infection are controversial. A murine model of K. pneumoniae was developed to address this important issue. Liver-associated TNF-alpha 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-alpha antibody. Interestingly, this reduction in liver injury failed to translate into improved survival. Mice receiving anti-TNF-alpha continued to succumb to the infection even out to day 10 postinfection. Bacterial clearance after TNF-alpha neutralization was significantly impaired at later time points during infection. Correlating with impaired bacterial clearance was diminished production of liver-associated MIP-2, MIP-1alpha, MCP-1, and interferon-gamma. Further evidence of diminished antibacterial immune responses was noted when the activational status of splenic natural killer cells in anti-TNF-alpha-treated mice was examined 24 h postinfection. Natural killer cells displayed decreased CD69 expression. Combined, these data indicate that the beneficial effects of TNF-alpha during systemic K. pneumoniae infection outweigh the detrimental effects of TNF-alpha-mediated hepatocyte cellular injury. Anti-TNF-alpha 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.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016470:Bacteremia / Q000276:immunology / Q000628:therapy*; D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression; D007694:Killer Cells, Natural / Q000276:immunology; D007710:Klebsiella Infections / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D007711:Klebsiella pneumoniae / Q000302:isolation & purification; D008099:Liver / Q000276:immunology / Q000293:injuries; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics
D000911:Antibodies, Monoclonal; D016207:Cytokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha