Reprogramming human T cells for disease tolerance in falciparum malaria

疟疾寄生虫通过蚊子传播，每年杀死数十万儿童。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，这些干预措施都不能100%有效地保护儿童免受感染。如果他们这样做，他们发生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。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，都加剧了这一问题。然而，我们知道，第一次感染后存活下来的儿童，即使再次感染相同数量或更多数量的寄生虫，也会迅速产生针对严重疾病的免疫力。因此，对严重疟疾的免疫力并不依赖于免疫系统能够杀死寄生虫，而是依赖于免疫系统能够容忍寄生虫的存在并限制感染造成的损害。因此，了解疟疾耐受性是如何起作用的，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于死于严重疟疾。由于在实地无法精确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安全控制的条件下在一年内三次感染疟疾寄生虫。在分析收集的血液样本时，我们发现志愿者在杀死疟疾寄生虫方面并没有得到任何改善-尽管他们感染了相同的克隆。志愿者还继续经历非常高水平的炎症，导致疟疾的标志性症状，如发烧。但至关重要的是，我们发现，在第一次感染期间，作为免疫反应关键协调者的T细胞被不加选择地激活。此外，有明确的肝损伤证据表明宿主组织受到广泛损害。相反，在再感染过程中T细胞的活化显著减少，并且没有观察到附带的组织损伤。在这项工作中，我们建议通过解决以下关键问题来解决参与疟疾再感染实验模型的人类志愿者中T细胞耐受性的机制：[1]活化的T细胞是否导致我们在首次感染中观察到的组织损伤？[2]这些T细胞在再感染时是如何关闭的[3]关闭大部分T细胞会阻止你产生抗寄生虫免疫力吗？[4]疟疾引起的耐受性是否抑制其他免疫反应（如对疫苗的免疫反应）？为了回答这些问题，我们将通过接种黄热病疫苗（以跟踪疟疾期间病毒特异性T细胞的命运），让我们的志愿者喝重水（这标志着T细胞被感染激活）并探索人体中最大的T细胞库-骨髓来推动控制人类疟疾感染的界限。通过了解耐受性是如何获得的（以及是否有任何有害后果），我们将首次能够利用这种防御策略的力量来确保儿童从疟疾中幸存下来。

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.