Correlation of histopathologic and bacteriologic changes with cytokine expression in an experimental murine model of bacteremic Staphylococcus aureus infection

Abstract

Staphylococcus aureus infections are often life threatening. Relatively little is known about the host response to these infections, in particular, the role played by cytokines. We established a mouse model of bacteremic S. aureus infection to correlate bacteriologic findings and pathologic changes with cytokine gene expression. Bacterial density in blood and tissue was highest at 1 h and minimal by 48 h. Despite the rapid clearance of bacteria, pathologic abnormalities and inflammatory cytokines were detected after clearance of the bacteria. The number of infiltrating inflammatory cells, as well as the size of inflammatory foci, increased with time. Interstitial accumulation of inflammatory cells and tissue damage, such as microabscesses, edema, and necrosis progressed following clearance of bacteria from the tissues. Levels of tumor necrosis factor and interleukin-1 protein in serum were detectable at 1 h and peaked at 4 h. Interleukin-6 protein expression showed different kinetics, with low levels detected at 1 h and increasing levels at 72 h postinfection. Tumor necrosis factor and the interleukins were expressed in inflammatory and noninflammatory cells in lung, liver, and heart tissues. Leukocytes in the infected tissues were highly reactive with antibodies to the three cytokines, suggesting that activated leukocytes are a major source of inflammatory cytokines after staphylococcal infection. Expression of interleukin-1 and interleukin-6 in tissue-specific cells and endothelial cells was also detected in infected tissues, indicating that cells other than leukocytes contribute to the elevated cytokine levels in this model. Once initiated, expression of inflammatory cytokines contributes to the pathogenesis of S. aureus disease.