Pretreatment Sublethal B. Anthracis Lethal Toxin in Rats

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In vitro the lethal factor component of B. anthracis LeTx inactivated mitogen-activated protein kinase kinases and inhibited TNFa and NO release in response to LPS and IFNg. Whether these anti-inflammatory effects are relevant to the pathogenicity of B. anthracis infection is not known. If they are however, we hypothesized that sublethal doses of LeTx might also have anti-inflammatory effects in vivo during lethal LPS challenge. In experiments, 3 h before a 24 h infusion with LPS, Sprague-Dawley rats with venous and arterial catheters were randomized to receive injections of low, medium or high sublethal doses of LeTx or diluent only. During LPS infusion, mean arterial blood pressure (MAP) (q1h) and plasma cytokines (IL-1a and b, IL-2, 4, 6, and 10, IFNg, TNFa, GM-CSF, MIP1,2 and 3a, and RANTES) and NO levels (2, 8, and 24 h) were measured. Animals were observed for 168 h. Compared to high doses of LeTx, medium and low doses caused decreases in the hazards ratio of survival approaching significance (p=0.08 for high vs low and medium doses combined). Compared to diluent only, LeTx decreased 10 of 12 cytokines at 2 h (none significantly), all 13 cytokines, 4 of them significantly or approaching it (IL-6, IL-10, IFNg, MIP2a,p<=0.08) at 8 h, and NO levels significantly from 2 to 24 h (p=0.02 for the effect of LeTx across time) and increased MAP significantly over the 24 h (p=0.001). Thus, consistent with in vitro data, sublethal LeTx decreased cytokine and NO levels in LPS challenged rats. This was associated with increased blood pressure and, with low and medium doses, beneficial survival trends. Whether these same anti-inflammatory effects with LeTx would be beneficial or instead impair host defense during bacterial infection requires further study. Studies are ongoing to investigate the effects of low sublethal doses of LeTx before E. coli infection in this rat model.