Sleep in malaria

疟疾中的睡眠

• 批准号: 444579901
• 负责人: Professorin Dr. Luciana Besedovsky
• 金额: --
• 依托单位: Institut für Medizinische Psychologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/444579901?language=en
• 关键词: Sleep; malaria

Infection with malaria parasites elicits sickness behavior with fatigue as a major symptom. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are potential mediators of this neurobehavioral response. As both cytokines are also sleep regulatory substances, an increase in slow wave sleep (SWS) duration and intensity during the symptomatic stage of malaria is very likely. Due to its immunosupportive properties, SWS in turn could boost host defense mechanisms and the formation of immunological memory against the pathogen. Analyses of sleep in malaria are at present completely lacking. We will therefore assess sleep changes (i) in patients with naturally acquired malaria in Lambaréné, Africa and (ii) in malaria-naive volunteers receiving controlled human malaria infection (CHMI) in Tübingen and will delineate whether these sleep changes can predict the clinical course of the infection and anti-malarial immunity, respectively. We hypothesize that malaria infected patients and participants with most pronounced increases in SWS duration and intensity have a shortened time until clearance of parasitemia and clinical symptoms and that participants with a boost in SWS after CHMI show more robust increases in malaria-specific effector T cells and antibodies. CHMI is a safe, highly standardized, ethically justifiable, and thus compelling experimental infection model in humans, that will also allow to identify potential mediators of sickness behavior and SWS changes, like e.g., TNF, prostaglandins or adenosine. In anti-malarial vaccination trials in Tübingen, we will moreover assess (iii) whether habitual good sleep benefits immunological memory formation. We expect that participants with habitual good SWS show higher malaria-specific T cells and antibodies in the effector and memory phase and higher protection rates upon subsequent CHMI. In an explorative manner we will additionally decipher whether sleep prepares the innate immune system for pathogen encounter the next day and whether this translates into more robust adaptive immunity. In sum, we aim to prove for the first time in humans that SWS is a host defense mechanism that is triggered by immune activation during an infection and in turn serves to optimize adaptive immunity against the pathogen. Apart from gaining knowledge into basic questions of sleep-immune research (Do infections trigger SWS in humans? What are the mediators? Does SWS benefit innate and adaptive immunity and immunological memory formation?) our findings will help to optimize diagnostic tools, vaccines and treatment in malaria.

感染疟疾寄生虫会引起以疲倦为主要症状的疾病行为。肿瘤坏死因子(TNF)和白介素1(IL-1)是这种神经行为反应的潜在介质。由于这两种细胞因子也是睡眠调节物质，在疟疾症状阶段，慢波睡眠(SWS)的持续时间和强度很可能增加。由于其免疫支持特性，SWS反过来可以增强宿主防御机制和形成对病原体的免疫记忆。目前完全缺乏对疟疾患者睡眠的分析。因此，我们将评估(I)非洲兰巴莱内自然获得性疟疾患者和(Ii)在图宾根接受受控人类疟疾感染(CHMI)的未感染疟疾的志愿者的睡眠变化，并将描述这些睡眠变化是否可以分别预测感染和抗疟疾免疫的临床过程。我们假设，疟疾感染患者和SWS持续时间和强度增加最明显的参与者在寄生虫血症和临床症状清除之前的时间较短，而CHMI后SWS增加的参与者在疟疾特异性效应T细胞和抗体方面表现出更强劲的增长。CHMI是一种安全的、高度标准化的、伦理上合理的、因此引人注目的人类实验感染模型，它还将允许识别疾病行为和SWS变化的潜在介质，如肿瘤坏死因子、前列腺素或腺苷。在Tübingen的抗疟疾疫苗接种试验中，我们还将评估(Iii)习惯良好的睡眠是否有助于免疫记忆的形成。我们预计，习惯性良好SWS的参与者在效应期和记忆期表现出更高的疟疾特异性T细胞和抗体，并在随后的CHMI中表现出更高的保护率。以探索性的方式，我们还将破译睡眠是否为第二天遇到病原体的先天性免疫系统做好了准备，以及这是否转化为更强大的适应性免疫。总之，我们的目标是首次在人类身上证明SWS是一种宿主防御机制，由感染期间的免疫激活触发，进而服务于优化针对病原体的适应性免疫。除了获得睡眠免疫研究的基本问题的知识外(感染是否会在人类中引发SWS？调解人是什么？SWS是否有益于先天和获得性免疫以及免疫记忆的形成？)我们的发现将有助于优化疟疾的诊断工具、疫苗和治疗。