Defective Innate Antibacterial Host Responses during Murine Klebsiella pneumoniae Bacteremia: Tumor Necrosis Factor (TNF) Receptor 1 Deficiency versus Therapy with Anti–TNF-α

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Abstract
Klebsiella pneumoniae is a leading cause of pneumonia due to gram-negative bacteria. A significant clinical complication of pulmonary infection with K. pneumoniae is peripheral blood dissemination, which results in a systemic infection coincident with the localized pulmonary infection. This study describes the critical importance of tumor necrosis factor (TNF) receptor 1 (TNFR1)—mediated signaling during K. pneumoniae bacteremia. TNFR1-deficient mice displayed a significantly increased mortality rate after intravenous inoculation. Unexpectedly, this increased mortality occurred in the absence of either increased bacterial burden or increased liver injury. However, excessive production of proinflammatory cytokines, including TNF-α, was observed in TNFR1-deficient mice, compared with that observed in infected C57BL/6 mice, which suggests that production was dysregulated in the absence of TNFR1 signaling. In contrast, other experiments examined the effect of immunotherapy with anti–TNF-α during K. pneumoniae bacteremia. Administration of a neutralizing anti–TNF-α antibody completely ablated K. pneumoniae—induced liver injury. This reduction in liver injury failed to translate into an improved survival rate, because mice died of the infection as late as 10 days after infection. Bacterial clearance after neutralization of TNF-α was significantly impaired at later time points during infection. Diminished production of liver-associated cytokines and chemokines correlated with impaired bacterial clearance, which suggests that antibacterial immune responses were dampened. These data indicate that the antibacterial host response is dysregulated in mice lacking TNFR1 or TNF-α bioactivity.

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