An integrated strategy for control of animal and plant parasitic nematodes through targeting MOD-1

线虫是一种简单的蛔虫，它们有着类似蠕虫的形状，但大小不一，从最小的微观物种到巨大的3米长的抹香鲸寄生蠕虫。它们相应地栖息在各种各样的栖息地，包括自由生物和寄生物种。自由生活的物种对生态系统有益。相比之下，寄生物种造成粮食生产的重大损失，也造成“被忽视的”人类热带病。现在控制这些线虫是一个特别及时的问题，原因有二：用于保护作物免受植物寄生线虫侵害的化学品对使用者和环境毒性极大，正在停止使用；与此同时，用于治疗动物寄生虫感染的药物正在失去效力，因为线虫正在产生耐药性。显然，需要一种方法来提供对环境影响小的化学品和以一种全新的方式来打破耐药性的药物。可以说，迄今为止最成功的杀线虫化合物是那些对线虫的神经肌肉系统有影响的化合物。这意味着蠕虫不能移动、进食或产卵，最终死亡。其中，最突出的化合物是伊维菌素。事实上，它的发现者获得了诺贝尔奖，因为这种化合物给兽医和人类医学带来了非凡的好处。它彻底改变了人类河盲症的治疗方法。一种类似伊维菌素的化学物质也用于作物保护，作为种子处理。伊维菌素成功的一个关键原因是它的选择性毒性，即它杀死寄生虫，但对哺乳动物宿主没有有害影响。它之所以能做到这一点，是因为它作用于一种叫做葡萄糖受体的离散信号分子，这种分子只存在于无脊椎动物中。因此，线虫具有这种受体，并被伊维菌素杀死，而脊椎动物哺乳动物宿主则不受伤害。不幸的是，经过三十多年的使用，对伊维菌素的耐药性已经出现，并且在治疗寄生虫方面是一个严重和日益严重的问题。此外，伊维菌素能杀死包括有益生物在内的多种无脊椎动物，因此对环境也有影响。我们已经找到了一个新的目标，不仅可以提供抗药化学物质，而且对有益的生态系统毒性更低。这一靶点是受体MOD-1，它首先在秀丽隐杆线虫的神经系统中被发现，在世界各地的实验室中被广泛用作寄生虫学的“模式”生物。重要的是，激活MOD-1通道会使秀丽隐杆线虫瘫痪，这表明靶向MOD-1的化学物质是杀线虫的。此外，阻断MOD-1会使植物寄生线虫失去功能，无法再进入根部。值得注意的是，MOD-1主要局限于线虫，在昆虫（如蜜蜂）中没有广泛发现，而在包括哺乳动物在内的高等动物中根本没有发现。这提供了一个令人信服的论点，即作用于MOD-1的化学物质在其选择性毒性方面具有良好的特征。它们可以用于兽医，在杀死寄生虫的同时对接受治疗的动物具有良好的耐受性，也可以用于作物保护，预防植物疾病，但保证传粉昆虫的安全。这个通道的生物学本质上是迷人的：我们将使用遗传学、药理学和分子模型来描述它，并在此过程中找到与MOD-1相互作用的化学物质。后者将解决农化部门和动物卫生部门对新的环境友好型寄生虫控制方法的迫切需要。

Nematodes are simple roundworms that share a similar worm-like shape yet range in size from the smallest microscopic species to a gigantic 3 metre long parasitic worm of sperm whale. They inhabit a correspondingly diverse range of habitats and include free-living and parasitic species. Free-living species are beneficial to the ecosystem. In contrast parasitic species cause major losses in food production and also 'neglected' human tropical diseases. The control of these nematodes is a particularly timely problem now for two reasons: The chemicals used to protect crops from plant parasitic nematodes are extremely toxic to users and the environment and are being withdrawn from use whilst at the same time drugs used to treat animal parasitic worm infections are losing their efficacy because nematodes are becoming resistant. Clearly, an approach is needed which will deliver chemicals that have low environmental impact and drugs that break resistance by acting in a completely new way. Arguably, the most successful nematicidal compounds to date have been those that have effects on the neuromuscular system of the worm. This means the worms can't move, feed or lay eggs and ultimately die. Of these, the most outstanding compound is ivermectin. Indeed, its discoverers won the Nobel Prize for the extraordinary benefit this compound has delivered to veterinary and human medicine. It revolutionised the treatment of human river blindness. An ivermectin-like chemical is also used in crop protection as a seed treatment. A key reason to the success of ivermectin is its selective toxicity i.e. it kills the parasite but has no detrimental effect on the mammalian host. It achieves this because it acts on a discrete signalling molecule, called a GluCl receptor that is only found in invertebrates. Therefore, the nematode worm has this receptor, and is killed by ivermectin, while the vertebrate mammalian host is unharmed. Unfortunately, due to more than three decades of use resistance to ivermectin has emerged and is a severe and increasing problem in the treatment of parasitic worms. Moreover, ivermectin kills a wide range of invertebrates including beneficial organisms and thus is not without environmental impact. We have found a new target that not only would deliver resistance-breaking chemicals but would also have lower toxicity to beneficial ecosystems. This target is the receptor MOD-1, first discovered in the nervous system of the nematode C. elegans that is widely used in laboratories around the world as a 'model' organism for parasitology. Importantly, activating the MOD-1 channel paralyses C. elegans showing that chemicals that target MOD-1 would be nematicidal. In addition, blocking MOD-1 disables plant parasitic nematodes and they can no longer enter roots. Notably, MOD-1 is largely restricted to the nematodes and is not widely found in insects e.g. in bees, and not at all in higher animals including mammals: This provides a compelling argument that chemicals that act on MOD-1 would have an excellent profile in terms of their selective toxicity. They could be deployed in veterinary medicine to kill the parasite whilst being well-tolerated by the animal receiving treatment and in crop protection to prevent plant disease but leave pollinating insects safe. The biology of this channel is intrinsically fascinating: We will characterise it using genetics, pharmacology and molecular modelling and in doing so find chemicals that interact with MOD-1. The latter will address the urgent need by both the agrochemical sector and the animal health sector for new environmentally friendly approaches to parasite control.