Elucidating the mechanism for malaria rhythmicity: an underlying circadian clock of the parasite

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Contact PD/PI: Rijo-Ferreira, Filipa Project Summary Malaria is a deadly parasitic disease. The major symptom for malaria is fever, which is associated with bursting of red blood cells (RBCs) upon completion of the cell cycle of the parasite. The parasite population coordinately ruptures the RBCs, reinvades new ones and replicates until their cycle is completed, and then a new burst of RBCs occurs. The result is a paroxysmal fever that recurs with the same periodicity as the parasite cell cycle: 48h or 72h for human-specific Plasmodium species and 24h for rodent-specific Plasmodium species. The mechanism for parasite synchronicity, which is central to this phenomenon, remains unknown. Despite the duration of cell cycle varying among Plasmodium species, it has a duration multiple of 24h, which led us to hypothesize that the mechanism for fever periodicity is an endogenous circadian clock of the parasite. Our preliminary data suggest that host nutritional status is the strongest signal for synchronizing the timing of bursting of red blood cells. But what mechanism leads to its 24h duration? Although rhythmic bursting of red blood cells is due to the parasite cell cycle, there seems to exist a circadian timekeeping mechanism that is independent of cell cycle, since my preliminary data suggest that even quiescent parasite-stages have 24h rhythms of gene expression. Circadian clocks regulate multiple physiological functions, from gene expression to behavior. Having circadian clocks that anticipate rhythmic changes in the environment is an evolutionary advantage for organisms. From bacteria to humans, mutations in clock components or desynchrony between the clock and the environment (chronic jet-lag) leads to reduced fitness, metabolic disruption and shorter lifespan. It has also been shown that a mismatch between the host and the parasite rhythms is detrimental for malaria parasite infection success, benefiting the host. The goal of this proposal is to determine the mechanism for Plasmodium synchronicity. To address this fundamental question, I will systematically dissect the contribution of the parasite cell cycle and systemic host signals to this phenomenon. With next-generation sequencing I aim to determine the rhythmic gene expression of the parasite when 1) diving into mammalian blood; 2) in a quiescent-stage; and 3) in the absence of systemic host signals in vitro. The latter will allow me to test whether these malaria rhythms are temperature compensated: a key feature of endogenous circadian rhythms. By decreasing temperature of cultured mammalian cells, their cell cycle duration slows down but their circadian clock remains with 24h. These studies will generate a comprehensive framework to resolve a long-standing question in the malaria field. More broadly, by dissecting whether the periodicity of fevers is driven by host signals or an internal circadian clock of the parasite, these studies will guide strategies to disrupt the synchronicity of the parasite and to the development of alternative approaches to tackle this deadly disease. Project Summary