An intrinsic oscillator drives the blood stage cycle of the malaria parasite
            <i>Plasmodium falciparum</i>

Smith, Lauren M.; Motta, Francis C.; Chopra, Garima; Moch, J. Kathleen; Nerem, Robert R.; Cummins, Bree; Roche, Kimberly; Kelliher, Christina M.; Leman, Adam R.; Harer, John; Gedeon, Tomáš; Waters, Norman C.; Haase, Steven B.

doi:10.1126/science.aba4357

Cited by 74 publications

(100 citation statements)

References 55 publications

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“…This range is insufficient to explain most of the variation in multiplication rates, and no significant correlation was shown here, but it could plausibly contribute a minor component of the variation and deserves future attention although other phases of the cycle may have a greater effect. The typical multiplication cycle length is considered to be 48 h, and this period was used as the nominal generation time for the standardised analysis of multiplication here, but actual duration of multiplication cycles have been shown to vary among several cultured clones by up to 1.5 fold 27 , 28 , so it would be interesting to investigate this parameter in clinical isolates. It is also possible that transcriptome analyses might identify genes that regulate mechanistic differences.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic multiplication rate variation and plasticity of human blood stage malaria parasites

et al. 2020

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Pathogen multiplication rate is theoretically an important determinant of virulence, although often poorly understood and difficult to measure accurately. We show intrinsic asexual blood stage multiplication rate variation of the major human malaria parasite Plasmodium falciparum to be associated with blood-stage infection intensity in patients. A panel of clinical isolates from a highly endemic West African population was analysed repeatedly during five months of continuous laboratory culture, showing a range of exponential multiplication rates at all timepoints tested, mean rates increasing over time. All isolates had different genome sequences, many containing within-isolate diversity that decreased over time in culture, but increases in multiplication rates were not primarily attributable to genomic selection. New mutants, including premature stop codons emerging in a few isolates, did not attain sufficiently high frequencies to substantially affect overall multiplication rates. Significantly, multiplication rate variation among the isolates at each of the assayed culture timepoints robustly correlated with parasite levels seen in patients at clinical presentation, indicating innate parasite control of multiplication rate that contributes to virulence.

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Section: Discussionmentioning

confidence: 99%

Intrinsic multiplication rate variation and plasticity of human blood stage malaria parasites

et al. 2020

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“…Similarly, daily oxidation-reduction rhythms exist within mammalian RBCs independent of a TTFL clock [45], are evolutionarily conserved [46] and may be linked to cellular flux in magnesium ions [47]. Recent work suggests that these rhythms are unlikely to impact on development during the IDC [9,24], but this is yet to be formally tested.…”

Section: Discussionmentioning

confidence: 99%

“…Determining how many cycles it will take a population of parasites to fully desynchronize is complex because the rate will be obscured by changes in density [ 33 ]. Thus, without sophisticated modelling that accounts for infection dynamics, it is difficult to determine whether desynchronization of the IDC, when hosts are in constant conditions, is due to a free-running oscillator belonging to the parasite [ 9 ]. Second, even in completely asynchronous infections, the expansion of parasite number due to each asexual stage replacing itself with multiple progeny can generate the illusion of strong synchrony [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

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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“…Aiming to investigate the rhythmic gene expression in parasites in absence of host cues, Smith et al 41 analyzed the gene expression from four different strains of P. falciparum. The authors showed that P. falciparum presents rhythmic gene expression, pointing out an intrinsic oscillator in the parasite.…”

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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An intrinsic oscillator drives the blood stage cycle of the malaria parasite Plasmodium falciparum

Cited by 74 publications

References 55 publications

Intrinsic multiplication rate variation and plasticity of human blood stage malaria parasites

Intrinsic multiplication rate variation and plasticity of human blood stage 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

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