Sleep in malaria

• Applicants: Professorin Dr. Luciana Besedovsky; Professor Dr. Benjamin G. Mordmüller
• Subject Area: Clinical Immunology and Allergology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 444579901

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.

• DFG Programme: Research Grants
• International Connection: Netherlands
• Co-Investigator: Professorin Dr. Tanja Lange