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的疾病之一，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蚊子的叮咬注射到受影响的个体中，并在人体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，寄生虫入侵人类血细胞并在其中分裂，每个血细胞中有一种寄生虫，两天后出现10到20种。细胞内的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类免疫系统的攻击，隐藏在宿主细胞中使它们能够避免被发现。然而，疟原虫会将少量的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，因为它会危及它们的检测，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功能。为了避免被发现，这些表面分子不是以单一拷贝的形式存在，而是以不同的蛋白质家族存在。这允许寄生虫在人类免疫系统学会识别它们的一个表面分子时做出反应，方法是切换到使用不同的、未被识别的分子。疟疾感染血细胞表面最常见的蛋白质是PIR蛋白质。到目前为止，所研究的所有类型的疟原虫都会产生PIRS，包括主要的人类感染疟疾寄生虫，恶性疟原虫和间日疟原虫。尽管我们对这些蛋白质在感染过程中扮演的角色知之甚少，但最近的研究已经给出了新的诱人的线索。在一项这样的研究中，疟疾感染是以老鼠为特征的。老鼠疟疾既可以是急性的，导致严重疾病，也可以是慢性的，具有长期、低水平的疾病。疟疾发病是否变得慢性或急性与哪些PIR蛋白表达有关。同时，两组不同的恶性疟原虫PIR蛋白(也被称为RIFIN)被发现与被称为抑制性免疫受体的人类分子结合。这些受体通过减少免疫细胞的作用来抑制人类的免疫反应，潜在地降低了这些细胞识别感染性病原体的能力。事实上，RIFIN与人类抑制性免疫受体LILRB1的结合减少了抗体的产生，这将使免疫系统的反应变得更慢。这些发现提出了一个令人兴奋的假设，即PIR蛋白会抑制人类的免疫系统，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，从而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，也不知道它们是如何与抑制性免疫受体结合的。这使得了解它们的功能以及它们如何影响人类免疫系统变得极其具有挑战性。如果没有这种洞察力，就很难将数百种PIR蛋白分类，也很难计算出每个组结合的是哪种人类受体。最后，如果不知道它们的结构，我们就不能理解PIR的哪些位相似，哪些位是可变的。如果我们希望训练免疫系统识别所有的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。这将帮助我们了解感染疟疾的血细胞表面最常见的蛋白质的作用，向我们展示它们是如何调节免疫系统的，并揭示我们是否可以在这些分子上找到一个不变的位置，作为我们消灭这种致命寄生虫的治疗靶点的一部分。

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.