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Delayed treatment with doxycycline has limited effect on anthrax infection in BLK57/B6 mice
John Kalns1, Julie Morris, Jeffrey Eggers
1Davis Hyperbaric Laboratory, USAFSAM/FEH, 2602 Louis Bauer Drive, Brooks City-Base, TX 78235-5252, USA. john.kalns@brooks.af.mil
Abstract:
Blk57/B6 mice were infected with LD90 dose of Sterne strain anthrax spores subcutaneously and then treated with doxycycline. Doxycycline at a dose of 1.5mg/kg, by intra-peritoneal injection, protected mice from death when given at the same time as spores. When doxycycline administration was delayed 4h survival is 90%. Delay of 24h increased survival time but had no impact on eventual mortality. When doxycycline was delayed 48h, mortality and time to death were comparable to sham injection. Peritoneal macrophages harvested from Blk57/B6 mice were examined for response to anthrax lethal toxin and are shown to be deficient in their ability to produce TNF-alpha and have increased expression of IL-6 compared to RAW 264.7 murine macrophage cell line. These findings suggest that antibiotic therapy has limited effects following lethal anthrax spore challenge, even when the host is of a phenotype that does not produce TNF-alpha in response to anthrax lethal toxin exposure.
Insights
Early doxycycline treatment protects mice against anthrax spores. However, delayed antibiotic therapy shows limited efficacy, even in mice with a specific immune response phenotype, highlighting challenges in anthrax treatment.
Area of Science:
- Microbiology
- Immunology
- Pharmacology
Background:
- Bacillus anthracis infection poses a significant biothreat.
- Understanding host-pathogen interactions and treatment efficacy is crucial.
Purpose of the Study:
- To evaluate the efficacy of doxycycline treatment in a murine model of anthrax spore infection.
- To investigate the impact of treatment delay on survival.
- To characterize the immune response of Blk57/B6 mice macrophages to anthrax lethal toxin.
Main Methods:
- Blk57/B6 mice were infected with Sterne strain anthrax spores and treated with doxycycline at varying time points.
- Survival rates and time to death were recorded.
- Peritoneal macrophages were isolated and analyzed for cytokine production (TNF-alpha, IL-6) upon exposure to anthrax lethal toxin.
Main Results:
- Doxycycline administered concurrently with spores provided complete protection.
- 90% survival was observed when treatment was delayed by 4 hours.
- Delayed treatment beyond 24 hours did not improve survival, with 48-hour delays resulting in mortality comparable to controls.
- Macrophages from Blk57/B6 mice showed reduced TNF-alpha and increased IL-6 production in response to lethal toxin.
Conclusions:
- Antibiotic therapy for anthrax spore infection has limited effectiveness when initiated late.
- The host's immune phenotype, specifically TNF-alpha deficiency, may influence treatment outcomes.
- Further research is needed to develop more effective anthrax treatment strategies.