Abstract
ABSTRACTBotulinum neurotoxin (BoNT) serotypes A, B and E are responsible for most cases of human botulism. The only approved therapy for botulism is antitoxin treatment administered to patients after symptom onset. However, a recent meta-analysis of antitoxin efficacy in human botulism cases over the past century concluded that a statistically significant reduction in mortality is associated with the use of type E and type A antitoxin, but not with type B antitoxin. Animal models could be highly valuable in studying postsymptom antitoxin efficacy (PSAE). However, the few attempts to evaluate PSAE in animals relied on subjective observations and showed ∼50% protection. Recently, we developed a novel spirometry model for the quantitative evaluation of PSAE in rabbits and used it to demonstrate full protection against BoNT/E. In the current study, a comparative evaluation of PSAE in botulism types A and B was conducted using this quantitative respiratory model. A lethal dose of each toxin induced a comparable course of disease both in terms of time to symptoms (TTS, 41.9±1.3 and 40.6±1.1 h, respectively) and of time to death (TTD, 71.3±3.1 and 66.3±1.7 h, respectively). However, in accordance with the differential serotypic PSAE observed in humans, postsymptom antitoxin treatment was fully effective only in BoNT/A-intoxicated rabbits. This serotypic divergence was reflected by a positive and statistically significant correlation between TTS and TTD in BoNT/A-intoxicated rabbits (r=0.91, P=0.0006), but not in those intoxicated with BoNT/B (r=0.06, P=0.88). The rabbit spirometry system might be useful in the evaluation toolkit of botulism therapeutics, including those under development and intended to act when antitoxin is no longer effective.
Highlights
Reduced minute volume is a cross-serotypic early symptom of botulism in rabbits The rabbit spirometry model was previously used to quantify early respiratory symptoms of type E botulism, which served as a clinical trigger to treat (Diamant et al, 2018)
To allow characterization of the respiration physiology in botulinumintoxicated rabbits, animals were exposed to 4 RbIMLD50 of Botulinum neurotoxin (BoNT)/A or BoNT/B and spirometry parameters were monitored preand postexposure
In accordance with the results obtained for BoNT/E, the earliest spirometry parameter deviation in both BoNT/A- and BoNT/B-intoxicated rabbits was observed in the minute volume (MV) parameter (TTS of 41.9±1.3 h and 40.6±1.1 h for BoNT/A and BoNT/B, respectively; Fig. 1)
Summary
Botulinum neurotoxins (BoNTs) produced by the anaerobic bacterium Clostridium botulinum are the most potent toxins known in nature, with an estimated human lethal dose 50%. BoNT serotypes A, B, E and, rarely, F are responsible for most cases of human botulism (Pirazzini et al, 2017). Widespread outbreaks of food-borne botulism might involve dozens of infected people who without adequate treatment could die (Kongsaengdao et al, 2006; McCarty et al, 2015; Weber et al, 1993); BoNTs pose a significant concern for health authorities. Owing to their extreme potency, BoNTs are classified as category A bio-threat agents (Centers for Disease Control and Prevention, https://emergency.cdc.gov/agent/agentlist-category.asp)
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