Structural studies of Plasmodium PIR proteins and their interactions with human inhibitory immune receptors

疟疾是影响人类的最致命疾病之一，每年导致约50万人死亡和数亿病例。它是由微小的疟原虫感染引起的。这些单细胞生物通过受感染的蚊子叮咬注入受影响的个体，并在人类肝脏和血液中发育和分裂。这种疾病的症状发生在感染的血液阶段。在这里，寄生虫侵入人体血细胞并在其中分裂，每个血细胞中有一个寄生虫，两天后有10到20个寄生虫出现。细胞内生活方式为这些寄生虫提供了主要优势。血液中的病原体不断受到人体免疫系统的攻击，隐藏在宿主细胞中使它们能够避免检测。然而，疟原虫将少量寄生虫分子发送到受感染的红细胞表面。这是一种危险的策略，因为它有被发现的风险，因此这些蛋白质在帮助寄生虫在受感染的人体内生存方面具有关键作用。为了避免被检测到，这些表面分子不是以单一拷贝存在，而是作为不同的蛋白质家族存在。当人类免疫系统学会识别疟原虫表面的一种分子时，疟原虫就会做出反应，转而使用一种不同的、未被识别的分子。在感染疟疾的血细胞表面最常见的蛋白质是PIR蛋白。迄今为止研究的所有类型的疟原虫寄生虫都产生PIR，包括主要的人类感染性疟疾寄生虫，恶性疟原虫和间日疟原虫。虽然我们对这些蛋白质在感染过程中所起的作用知之甚少，但最近的研究提供了新的诱人的线索。在一项这样的研究中，疟疾感染在小鼠中进行了表征。鼠疟可以是急性的，导致严重的疾病，也可以是慢性的，长期的，低水平的疾病。疟疾发作是否变成慢性或急性与PIR蛋白的表达有关。同时，发现两组不同的恶性疟原虫PIR蛋白（也称为RIFIN）与称为抑制性免疫受体的人类分子结合。这些受体通过降低免疫细胞的作用来抑制人体免疫反应，从而可能降低这些细胞识别感染因子的能力。事实上，RIFIN与人抑制性免疫受体LILRB1的结合减少了抗体的产生，这将使免疫系统的反应性降低。这些发现提出了一个令人兴奋的假设，即PIR蛋白抑制人体免疫系统，降低其检测和摧毁寄生虫的能力。这将有助于寄生虫的生存和个体之间的传播，导致更多的疟疾病例。值得注意的是，没有人知道PIR蛋白是什么样子的，或者它们如何与抑制性免疫受体结合。这使得了解它们如何发挥作用以及它们如何影响人类免疫系统变得非常具有挑战性。如果没有这种洞察力，就很难将数百种PIR蛋白归类，或者找出每一组与哪种人类受体结合。最后，如果不知道它们的结构，我们就无法理解PIR的哪些位是相似的，哪些是可变的。如果我们希望训练免疫系统识别所有PIR蛋白，那么我们需要能够找到它们的不变部分。因此，这笔资金将使我们能够解决这些问题，了解PIR的结构，功能和可变性。这将帮助我们了解疟疾感染血细胞表面最常见的蛋白质的作用，向我们展示它们如何调节免疫系统，并揭示我们是否可以在这些分子上找到一个不变的位点，我们可以在治疗上靶向它，作为我们寻求摧毁这种致命寄生虫的一部分。

Malaria is one of the most deadly diseases to affect mankind, leading to around half a million deaths and hundreds of millions of cases each year. It is caused by infection with tiny Plasmodium parasites. These single celled organisms are injected into affected individuals through the bite of an infected mosquito and develop and divide within the human liver and blood. The symptoms of the disease occur during the blood stage of infection. Here the parasites invade human blood cells and divide within them, with one parasite entering each blood cell and ten to twenty emerging two days later. An intracellular life style provides these parasites with major advantages. Pathogens within the blood are under constant attack from the human immune system and concealment within a host cell allows them to avoid detection. However, Plasmodium send a small number of parasite molecules to the surfaces of infected red blood cells. This is a dangerous strategy, as it risks their detection, and so these proteins have critical functions in helping the parasites to survive within the infected human. To help avoid detection, these surface molecules are not present in single copies, but as diverse protein families. This allows the parasite to respond when the human immune system learns to recognise one of their surface molecules by switching to use a different, unrecognised molecule.The most commonly found proteins on the surfaces of malaria-infected blood cells are the PIR proteins. All types of Plasmodium parasites studied so far produce PIRs, including the major human-infective malaria parasites, Plasmodium falciparum and Plasmodium vivax. Although we know remarkably little about the roles that these proteins play during infection, recent studies have given new and tantalizing clues. In one such study, malaria infection was characterised in mice. Mouse malaria can either be acute, leading to severe illness, or chronic, with long term, low level disease. Whether the malaria episode became chronic or acute correlated with which of the PIR proteins was expressed. In parallel, two different groups of Plasmodium falciparum PIR proteins (also known as RIFINs) were found to bind to human molecules know as inhibitory immune receptors. These receptors dampen the human immune response by reducing the effects of immune cells, potentially reducing the capacity of these cells to recognise infectious agents. Indeed, binding of RIFINs to the human inhibitory immune receptor, LILRB1, reduced antibody production, which will make the immune system less responsive. These findings suggest the exciting hypothesis that the PIR proteins dampen the human immune system, reducing its ability to detect and destroy the parasite. This would aid parasite survival and transmission between individuals, causing more malaria cases. Remarkably, no-one knows what a PIR protein looks like or how they bind to inhibitory immune receptors. This makes it extremely challenging to understand how they function and how they affect the human immune system. Without this insight it is hard to classify the hundreds of PIR proteins into groups or to work out which human receptor each group binds. Finally, without knowing their structures, we cannot understand which bits of the PIRs are similar and which are variable. If we wish to train the immune system to recognise all PIR proteins, then we need to be able to find their invariant parts. This funding will therefore allow us to address these questions, understanding the structures, functions and variability of the PIRs. This will help us to understand the role of the most commonly found protein on the surface of the malaria-infected blood cells, showing us how they modulate the immune system and revealing whether we can find an invariant site on these molecules which we can target therapeutically to as part of our quest to destroy this deadly parasite.