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Inhalational Poisoning by Botulinum Toxin and Inhalation Vaccination with Its Heavy-Chain Component

机译：肉毒杆菌毒素吸入中毒及其重链成分的接种疫苗

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Botulinum toxin is the etiologic agent responsible for the disease botulism, which is characterized by peripheral neuromuscular blockade. Botulism is ordinarily encountered as a form of oral poisoning. The toxin is absorbed from the lumen of the gut to reach the general circulation and is then distributed to peripheral cholinergic nerve endings. However, there is a widespread presumption that botulinum toxin can also act as an inhalation poison, which would require that it be absorbed from the airway. Experiments have been done to show that both pure toxin and progenitor toxin (a complex with auxiliary proteins) are inhalation poisons. Interestingly, the data indicate that auxiliary proteins are not necessary to protect the toxin or to facilitate its absorption. When studied on rat primary alveolar epithelial cells or on immortalized human pulmonary adenocarcinoma (Calu-3) cells, botulinum toxin displayed both specific binding and transcytosis. The rate of transport was greater in the apical-to-basolateral direction than in the basolateral-to-apical direction. Transcytosis was energy dependent, and it was blocked by serotype-specific antibody. The results demonstrated that the holotoxin was not essential for the process of binding and transcytosis. Both in vivo and in vitro experiments showed that the heavy-chain component of the toxin was transported across epithelial monolayers, which indicates that the structural determinants governing binding and transcytosis are found in this fragment. The heavy chain was not toxic, and therefore it was tested for utility as an inhalation vaccine against the parent molecule. This fragment was shown to evoke complete protection against toxin doses of at least 104 times the 50% lethal dose.
机译：肉毒杆菌毒素是引起肉毒中毒的病原体，其特征在于周围神经肌肉阻滞。肉毒杆菌中毒通常是口服中毒的一种形式。毒素从肠腔吸收，到达全身循环，然后分配到外周胆碱能神经末梢。然而，普遍认为肉毒杆菌毒素也可以作为吸入毒物，这将需要从呼吸道吸收。实验表明纯毒素和祖毒素（与辅助蛋白复合）都是吸入性毒物。有趣的是，数据表明辅助蛋白对于保护毒素或促进其吸收不是必需的。当在大鼠原发性肺泡上皮细胞或永生化的人肺腺癌（Calu-3）细胞上进行研究时，肉毒杆菌毒素同时表现出特异性结合和胞吞作用。顶侧到基底外侧方向的运输速率大于底侧到顶端方向的运输速率。转胞吞作用是能量依赖性的，并被血清型特异性抗体阻断。结果表明，全毒素对于结合和胞吞作用不是必需的。体内和体外实验均表明，毒素的重链组分跨过上皮单层运输，这表明在该片段中发现了控制结合和转胞吞作用的结构决定簇。重链无毒，因此经过测试可作为针对母体分子的吸入疫苗使用。该片段显示出对50％致死剂量至少10 4 毒素剂量的完全保护。

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