Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, USA.
Infect Immun. 2012 Dec;80(12):4133-42. doi: 10.1128/IAI.00669-12. Epub 2012 Sep 10.
Botulinum toxin is a highly potent oral and inhalation poison, which means that the toxin must have an efficient mechanism for penetration of epithelial barriers. To date, three models for toxin passage across epithelial barriers have been proposed: (i) the toxin itself undergoes binding and transcytosis; (ii) an auxiliary protein, HA35, transports toxin from the apical to the basal side of epithelial cells; and (iii) an auxiliary protein, HA35, acts on the basal side of epithelial cells to disrupt tight junctions, and this permits paracellular flux of toxin. These models were evaluated by studying toxin absorption following inhalation exposure in mice. Three types of experiments were conducted. In the first, the potency of pure neurotoxin was compared with that of progenitor toxin complex, which contains HA35. The results showed that the rate and extent of toxin absorption, as well as the potency of absorbed toxin, did not depend upon, nor were they enhanced by, the presence of HA35. In the second type of experiment, the potencies of pure neurotoxin and progenitor toxin complex were compared in the absence or presence of antibodies on the apical side of epithelial cells. Antibodies directed against the neurotoxin protected against challenge, but antibodies against HA35 did not. In the final type of experiment, the potency of pure neurotoxin and toxin complex was compared in animals pretreated to deliver antibodies to the basal side of epithelial cells. Once again, antibodies directed against the neurotoxin provided resistance to challenge, but antibodies directed against HA35 did not. Taken collectively, the data indicate that the toxin by itself is capable of crossing epithelial barriers. The data do not support any hypothesis in which HA35 is essential for toxin penetration of epithelial barriers.
肉毒杆菌毒素是一种高效的口服和吸入性毒物，这意味着该毒素必须有一种有效的机制来穿透上皮屏障。迄今为止，已经提出了三种跨上皮屏障的毒素传递模型：（i）毒素本身发生结合和转胞吞作用；（ii）辅助蛋白 HA35 将毒素从上皮细胞的顶侧向基底侧运输；（iii）辅助蛋白 HA35 作用于上皮细胞的基底侧，破坏紧密连接，从而允许毒素经细胞旁途径流动。这些模型通过研究吸入暴露后小鼠的毒素吸收来评估。进行了三种类型的实验。在第一项实验中，比较了纯神经毒素与含有 HA35 的前体毒素复合物的效力。结果表明，毒素的吸收速率和程度以及吸收毒素的效力不依赖于 HA35 的存在，也不受其增强。在第二种类型的实验中，比较了纯神经毒素和前体毒素复合物在缺乏或存在上皮细胞顶侧抗体的情况下的效力。针对神经毒素的抗体可提供保护，但针对 HA35 的抗体则不能。在最后一种类型的实验中，比较了在预处理后将抗体递送至上皮细胞基底侧的动物中纯神经毒素和毒素复合物的效力。再次，针对神经毒素的抗体提供了对挑战的抗性，但针对 HA35 的抗体则没有。总的来说，数据表明毒素本身能够穿过上皮屏障。数据不支持 HA35 对毒素穿透上皮屏障至关重要的任何假说。
