Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid

Prior, Kimberley F.; Middleton, Benita; Owolabi, Alíz T.Y.; Westwood, Mary L.; Holland, Jacob; O’Donnell, Aidan J.; Blackman, Michael J.; Skene, Debra J.; Reece, Sarah E.

doi:10.1101/2020.08.24.264689

Cited by 6 publications

(6 citation statements)

References 54 publications

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“…the duration of the division phase (Figure 2B). Indeed, several conditions have been described that delay schizogony onset (Babbitt et al, 2012;van Biljon et al, 2018;Prior et al, 2020). Time lapse imaging shows that the length of schizogony can vary from 12 to 16 hours (Klaus et al, 2021).…”

Section: Final Number Of Merozoites Could Be Regulated By Cell Cycle Timingmentioning

confidence: 99%

“…If removed prior to schizogony a dormancy-like state is induced, which can be rescued up to 72h later (McLean and Jacobs-Lorena, 2020). Coherently, isoleucine has been postulated as one of the key factors sensed by the parasite for synchronization (Prior et al, 2020). A similar reversible arrest can be induced by addition of DL-a-difluoromethylornithine, which prevents synthesis of polyamines (van Biljon et al, 2018).…”

Section: Influence Of Extrinsic Factors On Progeny Numbermentioning

confidence: 99%

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How Many Is Enough? - Challenges of Multinucleated Cell Division in Malaria Parasites

Simon

Stürmer

Guizetti

2021

Front. Cell. Infect. Microbiol.

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Regulating the number of progeny generated by replicative cell cycles is critical for any organism to best adapt to its environment. Classically, the decision whether to divide further is made after cell division is completed by cytokinesis and can be triggered by intrinsic or extrinsic factors. Contrarily, cell cycles of some species, such as the malaria-causing parasites, go through multinucleated cell stages. Hence, their number of progeny is determined prior to the completion of cell division. This should fundamentally affect how the process is regulated and raises questions about advantages and challenges of multinucleation in eukaryotes. Throughout their life cycle Plasmodium spp. parasites undergo four phases of extensive proliferation, which differ over three orders of magnitude in the amount of daughter cells that are produced by a single progenitor. Even during the asexual blood stage proliferation parasites can produce very variable numbers of progeny within one replicative cycle. Here, we review the few factors that have been shown to affect those numbers. We further provide a comparative quantification of merozoite numbers in several P. knowlesi and P. falciparum parasite strains, and we discuss the general processes that may regulate progeny number in the context of host-parasite interactions. Finally, we provide a perspective of the critical knowledge gaps hindering our understanding of the molecular mechanisms underlying this exciting and atypical mode of parasite multiplication.

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Section: Final Number Of Merozoites Could Be Regulated By Cell Cycle Timingmentioning

confidence: 99%

Section: Influence Of Extrinsic Factors On Progeny Numbermentioning

confidence: 99%

How Many Is Enough? - Challenges of Multinucleated Cell Division in Malaria Parasites

Simon

Stürmer

Guizetti

2021

Front. Cell. Infect. Microbiol.

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“…For example, perhaps mistimed IDC stages starve and die because host rhythms create an environment in which only certain stages survive at certain times of day. Most evidence suggests that malaria parasites (at least in large part) control their timing 4,25,32‐34 . This includes observations that P .…”

Section: Introductionmentioning

confidence: 99%

“…chabaudi and P . falciparum use a cue with a daily rhythm (isoleucine) to break IDC dormancy 34,36 . A key step in differentiating between the relative contributions of traits encoded by the genes of hosts vs parasites is to search for time‐keeping mechanisms in parasites.…”

Section: Introductionmentioning

confidence: 99%

Mistimed malaria parasites re‐synchronize with host feeding‐fasting rhythms by shortening the duration of intra‐erythrocytic development

O’Donnell

Greischar

Reece

2021

Parasite Immunology

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Aims Malaria parasites exhibit daily rhythms in the intra‐erythrocytic development cycle (IDC) that underpins asexual replication in the blood. The IDC schedule is aligned with the timing of host feeding‐fasting rhythms. When the IDC schedule is perturbed to become mismatched to host rhythms, it readily reschedules but it is not known how. Methods We intensively follow four groups of infections that have different temporal alignments between host rhythms and the IDC schedule for 10 days, before and after the peak in asexual densities. We compare how the duration, synchrony and timing of the IDC differs between parasites in control infections and those forced to reschedule by 12 hours and ask whether the density of parasites affects the rescheduling process. Results and conclusions Our experiments reveal parasites shorten the IDC duration by 2–3 hours to become realigned to host feeding‐fasting rhythms with 5–6 days, in a density‐independent manner. Furthermore, parasites are able to reschedule without significant fitness costs for them or their hosts. Understanding the extent of, and limits on, plasticity in the IDC schedule may reveal targets for novel interventions, such as drugs to disrupt IDC regulation and preventing IDC dormancy conferring tolerance to existing drugs.

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“…If novel drugs can be developed to disrupt the alignment between the IDC schedule and host rhythms (e.g. by modulating nutrient sensing by the parasite [ 64 ]), then administering such drugs alongside the first dose of traditional antimalarials might render subsequent doses targeting trophozoites, more effective.…”

Section: Discussionmentioning

confidence: 99%

Daily rhythms of both host and parasite affect antimalarial drug efficacy

Owolabi

Reece

Schneider

2021

Evolution, Medicine, and Public Health

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Background and objectives Circadian rhythms contribute to treatment efficacy in several non-communicable diseases. However, chronotherapy (administering drugs at a particular time-of-day) against infectious diseases has been overlooked. Yet, the daily rhythms of both hosts and disease-causing agents can impact the efficacy of drug treatment. We use the rodent malaria parasite Plasmodium chabaudi, to test if the daily rhythms of hosts, parasites, and their interactions, affect sensitivity to the key antimalarial, artemisinin. Methodology Asexual malaria parasites develop rhythmically in the host’s blood, in a manner timed to coordinate with host daily rhythms. Our experiments coupled or decoupled the timing of parasite and host rhythms, and we administered artemisinin at different times of day to coincide with when parasites were either at an early (ring) or later (trophozoite) developmental stage. We quantified the impacts of parasite developmental stage, and alignment of parasite and host rhythms, on drug sensitivity. Results We find that rings were less sensitive to artemisinin than trophozoites, and this difference was exacerbated when parasite and host rhythms were misaligned, with little direct contribution of host time-of-day on its own. Furthermore, the blood concentration of haem at the point of treatment correlated positively with artemisinin efficacy but only when parasite and host rhythms were aligned. Conclusions and implications Parasite rhythms influence drug sensitivity in vivo. The hitherto unknown modulation by alignment between parasite and host daily rhythms suggests that disrupting the timing of parasite development could be a novel chronotherapeutic approach. Lay Summary We reveal that chronotherapy (providing medicines at a particular time-of-day) could improve treatment for malaria infections. Specifically, parasites’ developmental stage at the time of treatment and the coordination of timing between parasite and host both affect how well antimalarial drug treatment works.

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Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid

Cited by 6 publications

References 54 publications

How Many Is Enough? - Challenges of Multinucleated Cell Division in Malaria Parasites

How Many Is Enough? - Challenges of Multinucleated Cell Division in Malaria Parasites

Mistimed malaria parasites re‐synchronize with host feeding‐fasting rhythms by shortening the duration of intra‐erythrocytic development

Daily rhythms of both host and parasite affect antimalarial drug efficacy

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