Bais Swarna, Churgin Matthew A, Fang-Yen Christopher, Greenberg Robert M
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS Negl Trop Dis. 2015 Dec 11;9(12):e0004295. doi: 10.1371/journal.pntd.0004295. eCollection 2015 Dec.
Schistosomiasis, caused by parasitic flatworms of the genus Schistosoma, is a neglected tropical disease affecting hundreds of millions globally. Praziquantel (PZQ), the only drug currently available for treatment and control, is largely ineffective against juvenile worms, and reports of PZQ resistance lend added urgency to the need for development of new therapeutics. Ion channels, which underlie electrical excitability in cells, are validated targets for many current anthelmintics. Transient receptor potential (TRP) channels are a large family of non-selective cation channels. TRP channels play key roles in sensory transduction and other critical functions, yet the properties of these channels have remained essentially unexplored in parasitic helminths. TRP channels fall into several (7-8) subfamilies, including TRPA and TRPV. Though schistosomes contain genes predicted to encode representatives of most of the TRP channel subfamilies, they do not appear to have genes for any TRPV channels. Nonetheless, we find that the TRPV1-selective activators capsaicin and resiniferatoxin (RTX) induce dramatic hyperactivity in adult worms; capsaicin also increases motility in schistosomula. SB 366719, a highly-selective TRPV1 antagonist, blocks the capsaicin-induced hyperactivity in adults. Mammalian TRPA1 is not activated by capsaicin, yet knockdown of the single predicted TRPA1-like gene (SmTRPA) in S. mansoni effectively abolishes capsaicin-induced responses in adult worms, suggesting that SmTRPA is required for capsaicin sensitivity in these parasites. Based on these results, we hypothesize that some schistosome TRP channels have novel pharmacological sensitivities that can be targeted to disrupt normal parasite neuromuscular function. These results also have implications for understanding the phylogeny of metazoan TRP channels and may help identify novel targets for new or repurposed therapeutics.
血吸虫病由血吸虫属的寄生扁虫引起，是一种被忽视的热带病，全球数亿人受其影响。吡喹酮（PZQ）是目前唯一可用于治疗和控制该病的药物，但对幼虫基本无效，而且有关于吡喹酮耐药性的报道，这使得开发新疗法的需求更加紧迫。离子通道是细胞电兴奋性的基础，是许多现有驱虫药已验证的靶点。瞬时受体电位（TRP）通道是一大类非选择性阳离子通道。TRP通道在感觉转导和其他关键功能中起关键作用，但这些通道的特性在寄生蠕虫中基本上尚未得到探索。TRP通道分为几个（7 - 8个）亚家族，包括TRPA和TRPV。虽然血吸虫含有预测可编码大多数TRP通道亚家族代表的基因，但它们似乎没有任何TRPV通道的基因。尽管如此，我们发现TRPV1选择性激活剂辣椒素和树脂毒素（RTX）可诱导成虫出现剧烈的多动；辣椒素还可增加童虫的活动能力。SB 366719是一种高度选择性的TRPV1拮抗剂，可阻断辣椒素诱导的成虫多动。哺乳动物的TRPA1不会被辣椒素激活，但在曼氏血吸虫中敲低单个预测的TRPA1样基因（SmTRPA）可有效消除辣椒素诱导的成虫反应，这表明SmTRPA是这些寄生虫对辣椒素敏感所必需的。基于这些结果，我们推测一些血吸虫TRP通道具有新的药理学敏感性，可作为靶点来破坏寄生虫正常的神经肌肉功能。这些结果对于理解后生动物TRP通道的系统发育也有意义，可能有助于确定新的或重新利用的治疗方法的新靶点。
