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

以MOD-1为靶点控制动植物寄生线虫的综合策略

• 批准号: BB/T002867/1
• 负责人: Lindy Holden-Dye
• 金额: $ 67.92万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT002867%2F1
• 关键词: integrated; strategy; control; animal; plant

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used to protect crops from plant parasitic nematodes are extremely toxic to users and the environment and are being withdrawn from use whilst at the same time drugs used to treat animal parasitic worm infections are losing their efficacy because nematodes are becoming resistant.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

线虫是一种简单的蛔虫，具有类似的蠕虫状形状，但大小范围从最小的微观物种到巨大的3米长的抹香鲸寄生虫。它们栖息在各种各样的生境中，包括自由生活和寄生物种。自由生活的物种对生态系统有益。与此相反，寄生虫物种造成粮食生产的重大损失，也造成“被忽视的”人类热带疾病。控制这些线虫是一个特别及时的问题，现在有两个原因：用于保护作物免受植物寄生线虫的化学品对用户和环境具有极强的毒性，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，我们需要一种方法来提供对环境影响小的化学品和以全新方式发挥作用的药物。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，因为这种化合物为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被用作作物保护的种子处理剂。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，由于超过三十年的使用，已经出现了对伊维菌素的耐药性，并且在寄生蠕虫的治疗中是一个严重且日益严重的问题。此外，伊维菌素杀死包括有益生物在内的多种无脊椎动物，因此并非没有环境影响。我们已经发现了一个新的目标，不仅可以提供破坏抗性的化学物质，而且对有益的生态系统的毒性也较低。这个靶点是受体MOD-1，它首先在线虫C的神经系统中发现。这种线虫在世界各地的实验室中被广泛用作寄生虫学的“模型”生物。重要的是，激活MOD-1通道会麻痹C。这表明针对MOD-1的化学物质是杀线虫的。此外，阻断MOD-1使植物寄生线虫失活，它们不能再进入根部。值得注意的是，M0 D-1主要限于线虫，并且在昆虫（例如蜜蜂）中不广泛发现，并且根本不在包括哺乳动物在内的高等动物中发现：这提供了一个令人信服的论点，即作用于M0 D-1的化学品在其选择性毒性方面将具有优异的特性。它们可以用于兽医学，以杀死寄生虫，同时被接受治疗的动物很好地耐受，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迷人的：我们将使用遗传学，药理学和分子建模来验证它，并在此过程中找到与MOD-1相互作用的化学物质。后者将解决农用化学品部门和动物卫生部门对新的无害环境的寄生虫控制办法的迫切需要。

项目成果

Cholinergic signaling at the body wall neuromuscular junction distally inhibits feeding behavior in Caenorhabditis elegans.

• DOI: 10.1016/j.jbc.2021.101466
• 发表时间: 2022-01
• 期刊: The Journal of biological chemistry
• 作者: Izquierdo PG;Calahorro F;Thisainathan T;Atkins JH;Haszczyn J;Lewis CJ;Tattersall JEH;Green AC;Holden-Dye L;O'Connor V
• 通讯作者: O'Connor V

Impact of drug solvents on C. elegans pharyngeal pumping.

• DOI: 10.1016/j.toxrep.2021.06.007
• 发表时间: 2021
• 期刊: Toxicology reports
• 作者: Calahorro F;Holden-Dye L;O'Connor V
• 通讯作者: O'Connor V

PharmacoGenetic targeting of a C. elegans essential neuron provides an in vivo screening for novel modulators of nematode ion channel function.

线虫必需神经元的药物遗传学靶向为线虫离子通道功能的新型调节剂提供了体内筛选。

• DOI: 10.1016/j.pestbp.2022.105152
• 发表时间: 2022
• 期刊: Pesticide biochemistry and physiology
• 影响因子: 4.7
• 作者: Calahorro F

Confounds of using the unc-58 selection marker highlights the importance of genotyping co-CRISPR genes.

• DOI: 10.1371/journal.pone.0253351
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Rawsthorne-Manning H;Calahorro F;G Izquierdo P;Tardy P;Boulin T;Holden-Dye L;O'Connor V;Dillon J
• 通讯作者: Dillon J