Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, Botulinum Research Center, 285 Old Westport Road, N Dartmouth, MA 02747, United States.
Biochem Biophys Res Commun. 2011 Feb 25;405(4):684-90. doi: 10.1016/j.bbrc.2011.01.102. Epub 2011 Feb 1.
Among the seven serotypes (A-G), type A botulinum neurotoxin (BoNT/A) is the most prevalent etiologic agent and the most potent serotype to cause foodborne botulism, characterized by flaccid muscle paralysis. Upon ingestion, BoNT/A crosses epithelial cell barriers to reach lymphatic and circulatory systems and blocks acetylcholine release at the pre-synaptic cholinergic nerve terminals of neuromuscular junctions (NMJs) resulting in paralysis. One of the unique features of BoNT/A intoxication is its neuroparalytic longevity due to its persistent catalytic activity. The persistent presence of the toxin inside the cell can induce host cell responses. To understand the pathophysiology and host response at the cellular level, gene expression changes upon exposure of human HT-29 colon carcinoma (epithelial) and SH-SY5Y neuroblastoma cell lines to BoNT/A complex were investigated using microarray analysis. In HT-29 cells, 167 genes were up-regulated while 60 genes were down-regulated, whereas in SH-SY5Y cells about 223 genes were up-regulated and 18 genes were down-regulated. Modulation of genes and pathways involved in neuroinflammatory, ubiquitin-proteasome degradation, phosphatidylinositol, calcium signaling in SH-SY5Y cells, and genes relevant to focal adhesion, cell adhesion molecules, adherens and gap junction related pathways in HT-29 cells suggest a massive host response to BoNT/A. A clear differential response in epithelial and neuronal cells indicates that the genes affected may play a distinct role in BoNTs cellular mode of action, involving these two types of host cells.
在七个血清型（A-G）中，A型肉毒梭菌神经毒素（BoNT/A）是最常见的病原体，也是导致食源性肉毒中毒的最有效血清型，其特征是肌肉松弛性瘫痪。摄入后，BoNT/A 穿过上皮细胞屏障到达淋巴和循环系统，并在运动终板的神经肌肉接头（NMJs）的前突触胆碱能神经末梢阻断乙酰胆碱释放，导致瘫痪。BoNT/A 中毒的一个独特特征是其神经瘫痪的持久性，这是由于其持续的催化活性。毒素在细胞内的持续存在会诱导宿主细胞反应。为了在细胞水平上了解 BoNT/A 中毒的病理生理学和宿主反应，使用微阵列分析研究了 BoNT/A 复合物暴露于人 HT-29 结肠癌细胞（上皮）和 SH-SY5Y 神经母细胞瘤细胞系后基因表达的变化。在 HT-29 细胞中，有 167 个基因上调，60 个基因下调，而在 SH-SY5Y 细胞中，大约 223 个基因上调，18 个基因下调。SH-SY5Y 细胞中参与神经炎症、泛素-蛋白酶体降解、磷脂酰肌醇、钙信号转导的基因和途径的调节，以及 HT-29 细胞中与焦点黏附、细胞黏附分子、黏着连接和缝隙连接相关途径相关的基因的调节，表明宿主对 BoNT/A 的强烈反应。上皮细胞和神经元细胞的明显差异反应表明，受影响的基因可能在 BoNTs 的细胞作用模式中发挥独特作用，涉及这两种宿主细胞。
