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

线虫是简单的蛔虫，有着类似蠕虫的形状，但大小不一，从最小的微型物种到巨大的3米长的抹香鲸寄生蠕虫。它们栖息在相应不同的栖息地，包括自由生活和寄生物种。自由生活的物种对生态系统有利。相比之下，寄生物种造成了粮食生产的重大损失，也“忽视”了人类的热带疾病。现在，控制这些线虫是一个特别及时的问题，原因有两个：用于保护作物免受植物寄生线虫侵袭的化学物质对使用者和环境具有极大的毒性，正在停止使用；同时，用于治疗动物寄生虫感染的药物正在失去效力，因为线虫正在产生抗药性。显然，需要一种方法，这种方法将提供对环境影响较小的化学品，并通过一种全新的方式提供打破耐药性的药物。可以说，迄今为止最成功的杀线虫化合物是那些对蠕虫的神经肌肉系统有影响的化合物。这意味着这些蠕虫不能移动、取食或产卵，最终会死亡。其中，最突出的化合物是伊维菌素。事实上，它的发现者因这种化合物为兽医和人类医学带来的非凡好处而获得诺贝尔奖。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离散的信号分子，称为GluCl受体，这种受体只在无脊椎动物中存在。因此，线虫有这种受体，并被伊维菌素杀死，而脊椎动物宿主没有受到伤害。不幸的是，由于三十多年的使用，对伊维菌素的耐药性已经出现，并成为寄生虫治疗中的一个严重且日益严重的问题。此外，伊维菌素可杀死包括有益生物在内的多种无脊椎动物，因此对环境也不是没有影响。我们已经发现了一种新的靶标，它不仅可以提供抗药性打破化学品，而且对有益的生态系统的毒性也会更低。这个靶标就是MOD-1受体，它最初是在线虫的神经系统中发现的，线虫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通道会使线虫瘫痪，表明针对MOD-1的化学物质将是杀线虫的。此外，阻断MOD-1使植物寄生线虫失效，它们不能再进入根部。值得注意的是，MOD-1在很大程度上仅限于线虫，在昆虫中并不广泛存在，例如在蜜蜂中，在包括哺乳动物在内的高等动物中根本不存在：这提供了一个令人信服的论点，即作用于MOD-1的化学物质将具有极好的选择性毒性。它们可以用于兽医，以杀死寄生虫，同时对接受治疗的动物具有良好的耐受性，并用于作物保护，以防止植物疾病，但使授粉昆虫安全。这个通道的生物学本质上是令人着迷的：我们将使用遗传学、药理学和分子模型来描述它，并在这样做的过程中找到与MOD-1相互作用的化学物质。后者将解决农用化学品部门和动物卫生部门对控制寄生虫的新的环境友好方法的迫切需要。

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used to protect crops from plant parasitic nematodes are extremely toxic to users and the environment and are being withdrawn from use whilst at the same time drugs used to treat animal parasitic worm infections are losing their efficacy because nematodes are becoming resistant.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.