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Correlation of histopathologic and bacteriologic changes with cytokine expression in an experimental murine model of
L Yao1, J W Berman, S M Factor
1Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
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.
Insights
Host immune responses to Staphylococcus aureus infections involve inflammatory cytokines. Even after bacteria are cleared, inflammation and tissue damage persist, driven by cytokines from leukocytes and other cells, contributing to disease severity.
Area of Science:
- Immunology
- Microbiology
- Pathology
Background:
- Staphylococcus aureus infections pose significant health risks.
- The host immune response, particularly the role of cytokines, is not well understood.
- Understanding cytokine involvement is crucial for managing severe S. aureus infections.
Purpose of the Study:
- To investigate the host response to bacteremic Staphylococcus aureus infection using a mouse model.
- To correlate bacterial clearance, pathological changes, and cytokine gene expression.
- To elucidate the cellular sources and temporal dynamics of key inflammatory cytokines.
Main Methods:
- Establishment of a mouse model for bacteremic S. aureus infection.
- Monitoring of bacterial density in blood and tissues over time (1h to 48h).
- Quantification of inflammatory cell infiltration, tissue damage, and cytokine (TNF, IL-1, IL-6) protein and gene expression.
Main Results:
- Bacterial load peaked at 1h and was minimal by 48h.
- Pathological abnormalities and inflammatory cytokines persisted after bacterial clearance.
- Inflammatory cell infiltration and tissue damage (microabscesses, edema, necrosis) increased over time.
- Tumor necrosis factor (TNF) and Interleukin-1 (IL-1) peaked at 4h, while Interleukin-6 (IL-6) increased by 72h.
- Cytokines were expressed by leukocytes, tissue-specific cells, and endothelial cells.
Conclusions:
- Host inflammatory responses, mediated by cytokines like TNF, IL-1, and IL-6, continue even after S. aureus clearance.
- Activated leukocytes are a primary source of these cytokines, but other cells also contribute.
- Cytokine expression plays a significant role in the pathogenesis of S. aureus infections.