The role of DAF-16 in driving the evolution of immunity mechanisms in nematodes

虽然获得性免疫(例如，抗体的产生)是脊椎动物(有脊椎的动物)所独有的，但在所有无脊椎动物中，甚至在植物(R基因，超敏反应)和细菌(限制性内切酶)中，都存在某种程度的先天免疫。因此，所有活着的有机体都有能力在分子水平上对感染性病原体做出反应。很明显，免疫系统必须在进化过程中迅速变化/病原体面临着进化出更有效的机制来感染宿主的压力，因此宿主必须进化出更有效的免疫机制来抵抗它们。鉴于此，人们可能会认为，密切相关的物种可能会在对不同病原体的抵抗力上表现出显著的差异。这确实是真的/例如，艾滋病毒会导致人类的一种致命疾病(艾滋病)，但对黑猩猩来说，如果有的话，是非常轻微的疾病。我们已经证明，这也适用于线虫(微型蠕虫)的物种。例如，真菌隐球菌会在四到五天内杀死线虫秀丽线虫，但杀死相关物种雷曼线虫需要三倍的时间。有趣的是，当测量未感染时的寿命时，也可以看到这种模式。如果这两种动物都保持在没有疾病的条件下，余氏梭子虫的寿命会更长，这表明免疫和寿命在分子水平上是相关的。我们推测，这种“联系”可能是由一种名为daf-16的“主调控”基因在免疫和长寿方面发挥的关键作用所致，该基因产生了相应的DAF-16蛋白。DAF-16帮助蠕虫在压力下存活；它触发解毒蛋白、免疫因子和帮助抵抗高温的蛋白(热休克蛋白)的产生。我们怀疑DAF-16及其控制的所谓“下游”基因是进化过程中可能发生改变的主要候选基因，要么通过操纵整个途径(例如，通过改变DAF-16的水平或活性)，要么通过改变个别成分(“下游”基因)。我们建议使用一组线虫物种来测试这一点，这些线虫都属于线虫属(即它们是姐妹种)。我们已经知道，这些物种对传染性病原体的敏感性不同，它们的自然寿命也不同。我们还知道它们都有daf-16基因，对于一个物种，我们知道它的下游的大多数基因。重要的是，DNA测序项目已经提供了该属两个物种(线虫和线虫)的全基因组序列，并将在短期内提供另外三个物种(线虫、线虫和一个尚未命名的物种PB2801)的全基因组序列。因此，我们处于一个独特的位置，能够探索进化如何塑造控制衰老和免疫的基因，因为这些物种是从另一个物种进化而来的。通过研究这一过程，我们希望更多地了解先天性免疫系统是如何工作的，以及进化是如何塑造这些免疫系统的。

Although adaptive immunity (the production of antibodies, for example) is unique to vertebrates (animals with backbones), some level of innate immunity is found in all invertebrates and indeed even in plants (R-genes, hypersensitive response) and in bacteria (restriction enzymes). Thus all living organisms have the ability to respond at the molecular level to infectious agents. It is clear that immune systems must change rapidly during evolution / pathogens are under pressure to evolve ever more effective mechanisms to infect their hosts, so the host must evolve ever more effective immune mechanisms to resist them. Given this, one might expect that species that are closely related may nonetheless show significant differences in their resistance to different pathogens. This is indeed true / HIV, for example, causes a fatal disease (AIDS) in humans but very mild, if any, illness in chimpanzees. We have shown that this also holds true for species of nematode (microscopic worms). For example, the fungus Cryptococcus kills the nematode Caenorhabditis elegans within four or five days, but takes three times as long to kill the related species Caenorhabditis remanei. Interestingly, this pattern is also seen when lifespan in the absence of infection is measured. If both animals are kept in disease-free conditions, C. remanei lives much longer, suggesting that immunity and longevity are linked at the molecular level. We hypothesise that this 'link' may result from the key role played in both immunity and longevity by one 'master regulator' gene, called daf-16, which makes the corresponding protein DAF-16. DAF-16 acts to help worms survive in times of stress; it triggers the production of detoxification proteins, immunity factors and proteins that help resist high temperatures ('heat-shock' proteins). We suspect that DAF-16, and the so-called 'downstream' genes that it controls, are prime candidates to be changed during evolution, either via manipulation of the whole pathway (for example, by changing the level or activity of DAF-16) or by changing individual components (the 'downstream' genes). We propose to test this by using a group of nematode species that all belong to the Caenorhabditis genus (i.e. they are 'sister' species). We already know that these species vary in their sensitivity to infectious pathogens and that they vary in their natural lifespan. We also know that they all have a daf-16 gene and, for one species, we know most of the genes that lie 'downstream' of it. Importantly, DNA-sequencing projects have provided the full ('whole genome') sequence for two species in the genus (C. elegans and C. briggsae) and will shortly provide whole genome sequences for three more (C. japonica, C. remanei and an as-yet unnamed species, PB2801). We are therefore in a unique position to be able to explore how evolution has shaped the genes that control ageing and immunity as these species have evolved from one another. By investigating this process, we hope to learn more both about how innate immune systems work, and how evolution shapes these immune systems.