Reprogramming human T cells for disease tolerance in falciparum malaria

重编程人类 T 细胞以提高恶性疟疾的抗病能力

• 批准号: MR/X005321/1
• 负责人: Philip Spence
• 金额: $ 264.1万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX005321%2F1
• 关键词: Reprogramming; human; cells; disease; tolerance

Malaria parasites are spread by mosquitoes and kill hundreds of thousands of children each year. Efforts to control malaria are focussed on stopping mosquitoes from biting (by spraying insecticides and sleeping under bednets) and reducing parasite numbers in the blood (using drugs or the recently licensed, partially effective malaria vaccine). Unfortunately, none of these interventions are 100% effective in protecting children from becoming infected. When they do, their risk of developing life-threatening complications is high, since severe malaria is most common during the first infection of life. The problem is exacerbated by the emergence of insecticide-resistant mosquitoes and drug-resistant parasites as well as quickly waning vaccine-induced immunity.However, we know that children who survive their first infection quickly develop immunity against severe forms of the disease - even if they are reinfected with the same or greater numbers of parasites. Immunity to severe malaria is thus not dependent on the immune system being able to kill parasites, but is instead underpinned by its ability to tolerate their presence and limit the damage the infection causes. Understanding how tolerance works in malaria would thus allow us to complement existing exposure control measures with a completely different strategy of host defense aimed at protecting the most vulnerable age-group from dying from severe malaria.Since it is impossible in the field to pinpoint when exactly a child is infected for the first time, we have started to study tolerance using an experimental medicine approach: healthy adult volunteers are infected with malaria parasites under safe controlled conditions three times over the course of a year. When analysing the blood samples collected, we have found that volunteers do not get any better at killing malaria parasites - despite being infected with the same clone. Volunteers also continue to experience very high levels of inflammation driving hallmark symptoms of malaria like fever. Crucially though, we have found that during first infection T cells, which are key orchestrators of the immune response, are indiscriminately activated. Furthermore there was clear evidence of liver injury indicating wide-spread damage of host tissue. In contrast, during reinfection T cell activation was dramatically reduced and no collateral tissue damage was observed.In this programme of work we are proposing to resolve the mechanism of T cell tolerance in human volunteers taking part in this experimental rechallenge model of malaria by addressing the following critical questions: [1] are activated T cells causing the tissue damage we observe in first infection? [2] how are these T cells switched off during reinfection? [3] does switching off the majority of T cells prevent you from developing anti-parasite immunity? [4] does malaria-induced tolerance suppress other immune responses (such as to vaccines)? To answer these questions we will push the boundaries of controlled human malaria infection by incorporating yellow fever vaccination (to track the fate of virus-specific T cells during malaria), giving our volunteers heavy water to drink (which marks T cells activated by infection) and exploring the biggest pool of T cells in the human body - the bone marrow. By understanding how tolerance is acquired (and whether there are any detrimental consequences) we will for the first time be able to harness the power of this defense strategy to ensure children survive malaria.

疟疾寄生虫通过蚊子传播，每年导致数十万儿童死亡。控制疟疾的努力集中在阻止蚊子叮咬(通过喷洒杀虫剂和睡在蚊帐下)和减少血液中的寄生虫数量(使用药物或最近获得许可的部分有效的疟疾疫苗)。不幸的是，在保护儿童免受感染方面，这些干预措施都不是100%有效的。当他们这样做时，他们患上危及生命的并发症的风险很高，因为严重的疟疾在生命的第一次感染期间最常见。随着抗药性蚊子和抗药性寄生虫的出现以及疫苗诱导的免疫力迅速减弱，这个问题变得更加严重。然而，我们知道，在第一次感染中幸存下来的儿童很快就会对严重形式的疾病产生免疫力--即使他们再次感染了相同或更多数量的寄生虫。因此，对严重疟疾的免疫力并不依赖于免疫系统是否能够杀死寄生虫，而是依赖于其容忍寄生虫存在和限制感染造成的损害的能力。因此，了解耐受性在疟疾中的作用将使我们能够用一种完全不同的宿主防御策略来补充现有的暴露控制措施，旨在保护最脆弱的年龄组免受严重疟疾的死亡。由于在现场不可能准确地确定儿童首次感染的确切时间，我们已经开始使用实验医学方法研究耐受性：健康的成年志愿者在一年的时间里在安全可控的条件下感染疟疾寄生虫三次。当分析采集的血液样本时，我们发现志愿者在杀死疟疾寄生虫方面并没有更好的表现--尽管感染了相同的克隆人。志愿者还继续经历非常高的炎症水平，导致疟疾的标志性症状，如发烧。然而，关键的是，我们发现在第一次感染期间，作为免疫反应的关键协调者的T细胞被不分青红皂白地激活。此外，有明确的肝脏损伤证据表明宿主组织广泛受损。相反，在再次感染期间，T细胞的激活显著减少，并且没有观察到附带的组织损伤。在这个工作计划中，我们建议通过解决以下关键问题来解决参与疟疾实验再挑战模型的人类志愿者的T细胞耐受机制：[1]激活的T细胞是否导致我们在首次感染时观察到的组织损伤？[2]这些T细胞在再次感染期间是如何被关闭的？[3]关闭大多数T细胞是否会阻止你形成抗寄生虫免疫？[4]疟疾诱导的耐受是否会抑制其他免疫反应(如疫苗)？为了回答这些问题，我们将通过纳入黄热病疫苗接种(追踪疟疾期间病毒特异性T细胞的命运)、给我们的志愿者喝重水(这标志着感染激活的T细胞)以及探索人体最大的T细胞池-骨髓，来突破人类疟疾感染控制的界限。通过了解耐受性是如何获得的(以及是否有任何有害的后果)，我们将首次能够利用这一防御战略的力量，确保儿童在疟疾中幸存下来。