Nematode surface properties and genetics, drug sensitivity and bacterial infection

动物的外表面是决定它如何与周围环境相互作用的主要因素。维持表面的完整性对于正常的发育和生存至关重要，因此表层提供了必要的保护，但它们也构成了病原体攻击的脆弱区域。我们正在研究细菌是如何感染动物的外部的，我们利用细菌感染来确定动物的最外层是如何形成并保持渗透性屏障的。我们还在研究这些外层是由什么构成的，以及动物如何应对和保护自己免受细菌感染。我们利用了一种非常简单的动物，叫做秀丽隐杆线虫，一种通常生活在土壤中的微小线虫。这种蠕虫为研究许多不同的生物学和医学问题提供了一个非常有用的实验室系统，因此世界上有500多个研究小组现在使用它作为实验系统。它的一些实验优势是非常便宜和容易生长，3天的一代时间允许快速的基因实验，并且它是完全透明的，因此可以直接观察活体动物的发育和疾病。最近，它已越来越多地用于研究细菌和真菌疾病的过程。我们已经发现了几种天然菌株，它们通过感染动物的外部来破坏或有效地杀死秀丽隐杆线虫。利用这些细菌，我们可以选择对感染有抵抗力的基因改变的蠕虫，并且已经发现了几十个参与第一次（感染）或疾病后续步骤的基因。事实证明，这些基因中的许多都是形成蠕虫不透水的表层所必需的，它们为我们提供了一条途径，来确定这层外层是由什么构成的，以及致病菌是如何附着在上面的。其他基因参与疾病的后期阶段，并提供如何检测致病菌的存在以及使用哪种抗菌防御的信息。蠕虫的部分防御反应包括动物体内某些细胞的显著扩大。研究这些细胞如何膨胀的分子机制为了解细胞在正常发育过程中如何改变形状和大小提供了基本的见解。在这种动物中观察渗透性和感染还有其他实际的原因。其中一个原因是，这种蠕虫提供了一种筛选新抗生素和药物的简便方法。因为动物很小，很容易处理，所以可以测试数百或数千种候选药物的效果，比用老鼠等方法便宜、快速和道德得多。新的抗生素和抗衰老药物，以及可以改善阿尔茨海默病或帕金森病的化合物，正在通过这种方式寻求。然而，许多对人类有效的候选药物可能对秀丽隐杆线虫无效，因为它们不能渗透到动物体内。这个问题可以通过使用我们研究的一些突变蠕虫来解决，因为它们的表面有漏洞，因此它们对药物治疗更敏感。我们打算开发一系列对药物敏感的蠕虫菌株，这将大大增加这些药物筛选的范围。第二个原因是，许多种类的线虫是重要的植物和动物寄生虫，在农业和林业中具有重要的经济意义，其中一些是重要的人类病原体，特别是在发展中国家——至少有10亿人患有线虫感染。秀丽隐杆线虫是一种方便无害的非寄生线虫，研究其对线虫特异性病原体的脆弱性可能为线虫的生物或化学控制提供新的途径。无论是在医药领域还是在农业领域，都严重缺乏良好的抗线虫药物。

The external surface of an animal is a major determinant of how it interacts with its surroundings. Maintaining surface integrity is essential for normal development and survival, so the surface layers provide essential protection, but they also constitute a vulnerable area for attack by pathogens. We are examining how bacteria infect the outside of an animal, and we use bacterial infections to determine how the outermost layers of this animal develop and maintain a permeability barrier. We are also studying what these outer layers are made of, and how the animal responds and defends itself against bacterial infection. We make use of a very simple animal called C. elegans, a tiny nematode worm which normally lives in the soil. This worm has provided a phenomenally useful laboratory system for studying many different biological and medical problems, and consequently well over 500 research groups around the world now use it as an experimental system. Some of its experimental advantages are that it is very cheap and easy to grow, with a 3 day generation time allowing for rapid genetic experiments, and it is wholly transparent, so that development and disease can be looked at directly in the living animal. Latterly, it has been increasingly used for studying processes of bacterial and fungal disease. We have discovered several natural bacterial strains which either damage or efficiently kill C. elegans worms, by infecting the outside of the animal. Using these bacteria, we can select for genetically altered worms that are resistant to infection, and have found dozens of genes that are involved in the first (infection) or subsequent steps in disease. Many of these genes turn out to be needed to make the impermeable surface coat of the worm, and they provide us with a route to establish what constitutes this outer layer, and how the pathogenic bacteria can attach to it. Other genes are involved in later disease stages, and provide information on how the presence of pathogenic bacteria is detected, and what kind of antibacterial defenses are used. Part of the worm's defense response involves a striking enlargement of certain cells within the animal. Studying the molecular mechanism of how these cells swell up provides basic insight into how cells can change their shape and size during normal development. There are additional practical reasons for looking at permeability and infection in this animal. One reason is that the worm provides an easy way of screening for new antibiotics and drugs. Because the animals are so small and so easily handled, it is possible to test hundreds or thousands of candidate drugs for effects, much more cheaply, speedily and ethically than by using mice, for example. Novel antibiotics and anti-ageing drugs, and compounds that would ameliorate Alzheimer or Parkinson disease, are being sought by this means. However, many candidate drugs that would work on humans are likely to be ineffective in C. elegans, because they fail to permeate into the animal. This problem may be overcome by using some of the mutant worms we work with, because their surfaces are leaky and consequently they are much more sensitive to drug treatments. We intend to develop a range of drug-sensitive worm strains that will greatly increase the scope of these drug screens. A second reason is that many nematode species of nematode are important plant and animal parasites, of great economic importance in agriculture and forestry, and some are significant human pathogens, especially in the developing world - at least a billion people suffer from nematode infections. Examining the vulnerabilities of C. elegans, a conveniently harmless and non-parasitic nematode, to nematode-specific pathogens, may offer new routes to biological or chemical control of nematodes. There is a severe lack of good anti-nematode drugs, both in medicine and in agriculture.