The malaria parasite has an intrinsic clock

Rijo‐Ferreira, Filipa; Acosta-Rodríguez, Victoria A.; Abel, John H.; Kornblum, Izabela; Bento, Inês; Kilaru, Gokhul; Klerman, Elizabeth B.; Mota, Maria M.; Takahashi, Joseph S.

doi:10.1126/science.aba2658

Cited by 74 publications

(122 citation statements)

References 64 publications

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“…Our results suggest that a product of food digestion schedules the IDC, supporting those of Prior et al [19] and Hirako et al [18], yet-at first glance-apparently contradicting two experiments, relating to food intake and infection of TTFLclock disrupted mice, respectively, in Rijo-Ferreira et al [10]. First, the food intake experiment in Rijo-Ferreira et al [10] aimed to test if the act of eating itself schedules the IDC. They infected WT mice housed in LD cycles, thus despite food provision being spread evenly throughout the day and night, these hosts retained their nocturnal lifestyle, including undergoing the bulk of metabolism at night.…”

Section: Discussionsupporting

confidence: 56%

“…Second, like our design, Rijo-Ferreira et al [10] gave TTFL-clock disrupted mice (Cry1/Cry2 null) food ad libitum and housed them in constant darkness, yet they found IDC rhythms (in infections started with synchronous parasites) remained strong. Rijo-Ferreira et al's [10] mice were kept in LD cycles until the point of infection which may allow residual rhythms generated by masking to persist for the first few days of infection. Indeed, when these TTFLclock disrupted hosts are housed in constant darkness for a week before infection, IDC rhythms do become dampened ( fig.…”

Section: Discussionmentioning

confidence: 94%

“…Indeed, when these TTFLclock disrupted hosts are housed in constant darkness for a week before infection, IDC rhythms do become dampened ( fig. 4L in Rijo-Ferreira et al) [10].…”

Section: Discussionmentioning

confidence: 97%

“…Our results suggest that a product of food digestion schedules the IDC, supporting those of Prior et al [ 19 ] and Hirako et al [ 18 ], yet—at first glance—apparently contradicting two experiments, relating to food intake and infection of TTFL-clock disrupted mice, respectively, in Rijo-Ferreira et al . [ 10 ]. First, the food intake experiment in Rijo-Ferreira et al .…”

Section: Discussionmentioning

confidence: 99%

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Host circadian clocks do not set the schedule for the within-host replication of malaria parasites

2020

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Circadian clocks coordinate organisms' activities with daily cycles in their environment. Parasites are subject to daily rhythms in the within-host environment, resulting from clock-control of host activities, including immune responses. Parasites also exhibit rhythms in their activities: the timing of within-host replication by malaria parasites is coordinated to host feeding rhythms. Precisely which host feeding-related rhythm(s) parasites align with and how this is achieved are unknown. Understanding rhythmic replication in malaria parasites matters because it underpins disease symptoms and fuels transmission investment. We test if rhythmicity in parasite replication is coordinated with the host's feeding-related rhythms and/or rhythms driven by the host's canonical circadian clock. We find that parasite rhythms coordinate with the time of day that hosts feed in both wild-type and clock-mutant hosts, whereas parasite rhythms become dampened in clock-mutant hosts that eat continuously. Our results hold whether infections are initiated with synchronous or with desynchronized parasites. We conclude that malaria parasite replication is coordinated to rhythmic host processes that are independent of the core-clock proteins PERIOD 1 and 2; most likely, a periodic nutrient made available when the host digests food. Thus, novel interventions could disrupt parasite rhythms to reduce their fitness, without interference by host clock-controlled homeostasis.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 94%

“…Indeed, when these TTFLclock disrupted hosts are housed in constant darkness for a week before infection, IDC rhythms do become dampened ( fig. 4L in Rijo-Ferreira et al) [10].…”

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Host circadian clocks do not set the schedule for the within-host replication of malaria parasites

2020

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“…Rijo-Ferreira et al 40 evaluated the impact of different factors in parasite rhythms by analyzing the transcriptome of rodent Plasmodium chabaudi parasites. They showed that parasites present a group of genes with rhythmic expression sustained in the absence of light, implying that parasites possess an intrinsic clock, and the host is not the only one to drive their cell cycle length.…”

Section: Discussionmentioning

confidence: 99%

The Plasmodium falciparum eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle

Dias

Nakabashi

Alves

et al. 2020

Journal of Pineal Research

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Melatonin and its indoles derivatives are central in the synchronization of malaria parasites. In this research, we discovered that melatonin is unable to increase the parasitemia in the human malaria Plasmodium falciparum that lacks the kinase PfeIK1. The PfeIK1 knockout strain is a valuable tool in the screening of indol‐related compound that blocks the melatonin effect in wild‐type (WT) parasite development. The assays were performed by using flow cytometry with simultaneous labeling for mitochondria viability with MitoTracker Deep Red and nucleus staining with SYBR Green. We found that Melatotosil leads to an increase in parasitemia in P. falciparum and blocks melatonin effect in the WT parasite. Using microscopy imaging system, we found that Melatotosil at 500 nM is able to induce cytosolic calcium rise in transgenic PfGCaMP3 parasites. On the contrary, the compound Triptiofen blocks P. falciparum cell cycle with IC50 9.76 µM ± 0.6, inhibits melatonin action, and does not lead to a cytosolic calcium rise in PfGCaMP3 parasites. We also found that the synthetic indol‐related compounds arrested parasite cycle for PfeIK1 knockout and (WT) P. falciparum (3D7) in 72 hours culture assays with the IC50 values slighting lower for the WT strain. We concluded that the kinase PfeIK1 is central for melatonin downstream signaling pathways involved in parasite cell cycle progression. More importantly, the indol‐related compounds block its cycle as an upstream essential mechanism for parasite survival. Our data clearly show that this class of compounds emerge as an alternative for the problem of resistance with the classical antimalarials.

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Coupled network of the circadian clocks: a driving force of rhythmic physiology

2020

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The circadian system is composed of coupled endogenous oscillators that allow living beings, including humans, to anticipate and adapt to daily changes in their environment. In mammals, circadian clocks form a hierarchically organized network with a ‘master clock’ located in the suprachiasmatic nucleus of the hypothalamus, which ensures entrainment of subsidiary oscillators to environmental cycles. Robust rhythmicity of body clocks is indispensable for temporally coordinating organ functions, and the disruption or misalignment of circadian rhythms caused for instance by modern lifestyle is strongly associated with various widespread diseases. This review aims to provide a comprehensive overview of our current knowledge about the molecular architecture and system‐level organization of mammalian circadian oscillators. Furthermore, we discuss the regulatory roles of peripheral clocks for cell and organ physiology and their implication in the temporal coordination of metabolism in human health and disease. Finally, we summarize methods for assessing circadian rhythmicity in humans.

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The malaria parasite has an intrinsic clock

Cited by 74 publications

References 64 publications

Host circadian clocks do not set the schedule for the within-host replication of malaria parasites

Host circadian clocks do not set the schedule for the within-host replication of malaria parasites

The Plasmodium falciparum eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle

Coupled network of the circadian clocks: a driving force of rhythmic physiology

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