Defining and Exploiting the Circadian Clocks in Malaria Parasites

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Project Summary | Abstract Malaria’s immense public health burden is undisputable with numbers of deaths increasing since 2020, however the mechanism for its characteristic rhythmic fevers remains poorly understood. Earth rotation has been a driving force for organisms to evolve circadian clocks to anticipate daily rhythms. In humans, circadian clocks regulate multiple physiological aspects of biology, including sleep-wake cycles, metabolism, and immune defense. Human’s circadian biology leads to body rhythms experienced by the pathogens that infect us. Malaria, a parasitic disease that kills over half a million people each year, is famous for its periodic fevers. Malarial periodic fevers are a consequence of the synchronous bursting of the host’s red blood cells, containing parasites and metabolic waste. It has long been assumed that malarial periodic fevers and the parasite replication rhythms that cause them were driven by the host’s own circadian rhythms. The existence and role of the malarial parasites’ intrinsic clocks has been unknown. Recent discoveries showed that malaria parasite rhythms are intrinsic. Parasite’s synchronous bursting persists even when infecting a circadian clock mutant arrhythmic host. However, the molecular regulation and functions of malaria clock remains elusive. This led to the hypothesis that the parasite clock is an essential component of parasite biology and a contributor to pathogenesis of parasitic diseases. The overall aim of this proposal is to decode the molecular processes that regulate circadian rhythms in parasites and discover how disrupting their regulatory networks impacts the pathogenesis of malaria and transmission. By using forward-genetics screens, behavioral, molecular and bioinformatic approaches, the molecular machinery of malaria parasites will be identified. This is an emerging new field of research of circadian rhythms in infectious diseases. The fact that multiple parasitic infections show daily rhythms further supports the hypothesis that circadian rhythm in parasites is essential for their biology, fitness and potentially transmission - and that deregulation of this biological rhythm may disrupt their well-orchestrated success in causing infections. This proposal will provide a foundation for discovering parasite clocks in other parasitic diseases such as toxoplasmosis and leishmaniasis. Beyond the significance of this work to basic parasitology discovery, it could also unravel insights on the disease pathogenesis by uncovering the mechanism for malaria’s main fever symptom. Parasitic diseases pose increasing threats to global public health and this innovative research will provide new targets to directly disrupt the rhythms that contribute to the disease.