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Differential host inflammatory responses to viable versus antibiotic-killed bacteria in experimental microbial sepsis
R Silverstein1, J G Wood, Q Xue
1Department of Biochemistry, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. rsilvers@kumc.edu
Abstract:
Staphylococcus aureus killed during imipenem or ceftazidime chemotherapy in mice elicited an early release of tumor necrosis factor alpha (TNF-alpha) into the systemic circulation. This response was coincident in time with an increase in leukocyte-endothelium adhesive interactions in the microvasculature. Equivalent responses were not observed without the antibiotic treatment (imipenem or ceftazidime). Protective efficacy of the same antibiotic treatment was markedly diminished in D-galactosamine-treated mice compared to controls; e.g., it dropped from 2,000-fold to 70-fold with 4 mg of imipenem per kg given at the time of challenge. Nevertheless, protection was quantitatively restored upon concurrent administration of neutralizing anti-TNF-alpha antibody or 4 mg of dexamethasone per kg to these TNF-alpha-hypersensitive mice. Importantly, protection afforded by dexamethasone was not seen when the animals were challenged with viable organisms but without the concurrent administration of antibiotic. An early TNF-alpha response could also be demonstrated upon challenge with Escherichia coli, but in this instance, neither the timing nor the magnitude of that response was influenced by treatment with these antibiotics. We conclude from these studies that the inflammatory response to viable versus killed bacteria may differ markedly depending on the particular bacterium, host sensitivity to TNF-alpha, and possibly the Gram stain classification.
Insights
Antibiotic treatment of Staphylococcus aureus in mice triggers tumor necrosis factor alpha (TNF-alpha) release, increasing inflammation. This response, crucial for antibiotic efficacy, can be modulated by host sensitivity and bacterial type.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- Antibiotic chemotherapy can paradoxically exacerbate inflammatory responses.
- Tumor necrosis factor alpha (TNF-alpha) plays a critical role in mediating inflammatory and immune responses.
- Understanding the interplay between antibiotics, bacterial components, and host immune mediators is crucial for effective treatment.
Purpose of the Study:
- To investigate the role of TNF-alpha in the host response to antibiotic-killed Staphylococcus aureus.
- To determine the influence of antibiotic treatment on TNF-alpha release and subsequent inflammatory events.
- To evaluate the impact of host sensitivity to TNF-alpha on antibiotic efficacy.
Main Methods:
- Mice were treated with imipenem or ceftazidime and challenged with killed Staphylococcus aureus.
- TNF-alpha levels and leukocyte-endothelium interactions were measured.
- Antibiotic efficacy was assessed in D-galactosamine-sensitized mice, with or without anti-TNF-alpha antibody or dexamethasone.
- Similar experiments were conducted using Escherichia coli.
Main Results:
- Antibiotic treatment of killed S. aureus induced early TNF-alpha release and increased leukocyte-endothelium adhesion.
- This inflammatory response was absent without antibiotic treatment.
- Antibiotic efficacy was significantly reduced in D-galactosamine-treated mice but restored by anti-TNF-alpha antibody or dexamethasone.
- E. coli challenge elicited TNF-alpha release, but it was not influenced by antibiotic treatment.
Conclusions:
- The inflammatory response to killed bacteria depends on the bacterium, host TNF-alpha sensitivity, and antibiotic treatment.
- Antibiotic-induced TNF-alpha release contributes to the host inflammatory response and influences therapeutic outcomes.
- Gram stain classification may also play a role in the differential host response to bacterial challenges.