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

疟原虫 PIR 蛋白的结构研究及其与人类抑制性免疫受体的相互作用

• 批准号: MR/T000368/1
• 负责人: Matthew Higgins
• 金额: $ 58.74万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT000368%2F1
• 关键词: Structural; studies; Plasmodium; PIR; proteins

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.

疟疾是影响人类最致命的疾病之一，每年大约有50万人死亡和数亿例。它是由微小疟原虫感染引起的。这些单细胞的生物通过咬伤被感染的蚊子注射到受影响的个体中，并在人肝脏和血液中发展和分裂。该疾病的症状发生在感染的血液阶段。在这里，寄生虫会侵入人体血细胞并在其中分裂，其中一个寄生虫进入每个血细胞，两天后出现了十到二十个。细胞内的生活方式为这些寄生虫提供了主要优势。血液中的病原体受到人类免疫系统的持续攻击，宿主细胞中的隐藏使它们避免检测。然而，疟原虫将少量的寄生虫分子发送到感染的红细胞的表面。这是一个危险的策略，因为它冒着检测风险，因此这些蛋白质在帮助寄生虫生存在受感染的人类中具有关键功能。为了避免检测，这些表面分子并不存在于单个拷贝中，而是作为多样化的蛋白质家族。当人类免疫系统学会通过切换到使用不同的，未识别的分子来识别其表面分子之一时，寄生虫可以做出反应。疟疾感染的血细胞表面上最常见的蛋白质是PIR蛋白。到目前为止研究的所有类型的疟原虫寄生虫都会产生pir，包括主要的人类感染疟疾寄生虫，恶性疟原虫和葡萄球菌。尽管我们对这些蛋白质在感染过程中所扮演的角色知之甚少，但最近的研究给出了新的和诱人的线索。在一项这样的研究中，小鼠的疟疾感染是表征的。小鼠疟疾可以急性，导致严重疾病或长期慢性疾病。无论疟疾发作变为慢性还是急性与表达的PIR蛋白相关。同时，发现两组不同的恶性疟原虫PIR蛋白（也称为Rifins）与人分子结合，称为抑制性免疫受体。这些受体通过减少免疫细胞的作用来抑制人的免疫反应，从而降低这些细胞识别感染剂的能力。实际上，利福丁与人抑制性免疫受体LILB1的结合减少了抗体的产生，这会使免疫系统的反应降低。这些发现表明，令人兴奋的假设是PIR蛋白会抑制人类免疫系统，从而降低其检测和破坏寄生虫的能力。这将有助于个人之间的寄生虫生存和传播，从而导致更多的疟疾病例。值得注意的是，没有人知道PIR蛋白的外观或它们如何与抑制性免疫受体结合。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为具有挑战性。没有这种见解，就很难将数百种PIR蛋白分类为基团，或者弄清每个人受体结合的人。最后，在不知道其结构的情况下，我们无法理解PIR的哪些位相似且哪些是可变的。如果我们希望训练免疫系统以识别所有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。这将有助于我们了解最常见的蛋白质在感染疟疾的血细胞表面上的作用，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，我们可以靶向治疗的靶向。作为我们寻求摧毁这个致命寄生虫的一部分。

项目成果

Rational structure-guided design of a blood stage malaria vaccine immunogen presenting a single epitope from PfRH5

具有 PfRH5 单一表位的血期疟疾疫苗免疫原的合理结构指导设计

• DOI: 10.1101/2024.02.29.582763
• 发表时间: 2024
• 作者: Harrison T

Structure of the Plasmodium-interspersed repeat proteins of the malaria parasite.

• DOI: 10.1073/pnas.2016775117
• 发表时间: 2020-12-15
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Harrison TE;Reid AJ;Cunningham D;Langhorne J;Higgins MK
• 通讯作者: Higgins MK