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

DAF-16在驱动线虫免疫机制进化中的作用

• 批准号: BB/F000138/1
• 负责人: Robin May
• 金额: $ 43.24万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF000138%2F1
• 关键词: role; DAF; 16; driving; evolution

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.

虽然适应性免疫（例如产生抗体）是脊椎动物（有脊骨的动物）所特有的，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，都发现了某种程度的先天免疫。因此，所有生物都有能力在分子水平上对感染因子作出反应。很明显，免疫系统在进化过程中必须迅速变化/病原体在压力下进化出更有效的机制来感染宿主，因此宿主必须进化出更有效的免疫机制来抵抗它们。考虑到这一点，人们可能会认为，近亲物种在对不同病原体的抵抗力方面可能会表现出显著的差异。这确实是对的。例如，艾滋病毒在人类身上会导致一种致命的疾病（艾滋病），但在黑猩猩身上却非常轻微，如果有的话。我们已经证明，这也适用于各种线虫（微观蠕虫）。例如，真菌隐球菌在四五天内杀死秀丽隐杆线虫，但杀死相关物种残余隐杆线虫需要三倍的时间。有趣的是，在没有感染的情况下，这种模式也可以被观察到。如果这两种动物都保持在无疾病的条件下，C. remanei活得更长，这表明免疫和长寿在分子水平上是联系在一起的。我们假设，这种“联系”可能是由于一个名为daf-16的“主调节”基因在免疫和长寿中发挥的关键作用，该基因产生相应的daf-16蛋白。DAF-16的作用是帮助蠕虫在压力下生存；它会触发解毒蛋白、免疫因子和有助于抵抗高温的蛋白质（“热休克”蛋白）的产生。我们怀疑DAF-16及其控制的所谓“下游”基因是进化过程中改变的主要候选者，要么通过操纵整个途径（例如，通过改变DAF-16的水平或活性），要么通过改变单个成分（“下游”基因）。我们建议通过使用一组都属于隐杆线虫属的线虫物种（即它们是“姐妹”物种）来测试这一点。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。我们也知道它们都有daf-16基因，对于一个物种，我们知道大多数基因位于它的下游。重要的是，dna测序项目已经为线虫属中的两个物种（秀丽隐杆线虫和briggsae线虫）提供了完整的（“全基因组”）序列，并将很快为另外三个物种（日本血吸虫、中国血吸虫和一个尚未命名的物种PB2801）提供全基因组序列。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，因为这些物种是从彼此进化而来的。通过研究这个过程，我们希望更多地了解先天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。

项目成果

Phenotypic covariance of longevity, immunity and stress resistance in the caenorhabditis nematodes.

• DOI: 10.1371/journal.pone.0009978
• 发表时间: 2010-04-01
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Amrit FR;Boehnisch CM;May RC
• 通讯作者: May RC

Protist-type lysozymes of the nematode Caenorhabditis elegans contribute to resistance against pathogenic Bacillus thuringiensis.

• DOI: 10.1371/journal.pone.0024619
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Boehnisch C;Wong D;Habig M;Isermann K;Michiels NK;Roeder T;May RC;Schulenburg H
• 通讯作者: Schulenburg H