A nuclear protein, PfMORC confers melatonin dependent synchrony of the human malaria parasite P. falciparum in the asexual stage

Singh, Maneesh; Tessarin-Almeida, Giulliana; Dias, Bárbara Karina de Menezes; Pereira, Pedro Scarpellli; Costa, Fahyme; Przyborski, Jude M.; Garcia, Célia Regina da Silva

doi:10.1038/s41598-021-81235-2

Cited by 19 publications

(32 citation statements)

References 53 publications

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“…To date, the only gene known to be involved in the IDC schedule is SR10, which modulates IDC duration in response to perturbations of host time-of-day ( Subudhi et al , 2020 ). Identifying KIN ( Mancio-Silva et al , 2017 ) regulated pathways and whether they, along with pathways associated with SR10 ( Subudhi et al , 2020 ), and PK7/MORC (which is involved in IDC stage transitions; Singh et al , 2021 ), are sensitive to isoleucine might reveal how the parasites’ time-keeping mechanism operates. Whilst by no means conclusive, our results feed the debate about whether malaria parasites keep time by an endogenous circadian oscillator or a simpler mechanism.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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Background: Rapid asexual replication of blood stage malaria parasites is responsible for the severity of disease symptoms and fuels the production of transmission forms. Here, we demonstrate that a Plasmodium chabaudi’s schedule for asexual replication can be orchestrated by isoleucine, a metabolite provided to the parasite in a periodic manner due to the host’s rhythmic intake of food. Methods: We infect female C57BL/6 and Per1/2-null mice which have a disrupted canonical (transcription translation feedback loop, TTFL) clock with 1×105 red blood cells containing P. chabaudi (DK genotype). We perturb the timing of rhythms in asexual replication and host feeding-fasting cycles to identify nutrients with rhythms that match all combinations of host and parasite rhythms. We then test whether perturbing the availability of the best candidate nutrient in vitro changes the schedule for asexual development. Results: Our large-scale metabolomics experiment and follow up experiments reveal that only one metabolite - the amino acid isoleucine – fits criteria for a time-of-day cue used by parasites to set the schedule for replication. The response to isoleucine is a parasite strategy rather than solely the consequences of a constraint imposed by host rhythms, because unlike when parasites are deprived of other essential nutrients, they suffer no apparent costs from isoleucine withdrawal. Conclusions: Overall, our data suggest parasites can use the daily rhythmicity of blood-isoleucine concentration to synchronise asexual development with the availability of isoleucine, and potentially other resources, that arrive in the blood in a periodic manner due to the host’s daily feeding-fasting cycle. Identifying both how and why parasites keep time opens avenues for interventions; interfering with the parasite’s time-keeping mechanism may stall replication, increasing the efficacy of drugs and immune responses, and could also prevent parasites from entering dormancy to tolerate drugs.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…To date, the only gene known to be involved in the IDC schedule is SR10, which modulates IDC duration in response to perturbations of host time-of-day (Subudhi et al, 2020). Identifying KIN (Mancio-Silva et al, 2017), regulated pathways whether they, along with pathways associated with SR10 (Subhudi et al, 2020), and PK7/MORC (which is involved in IDC stage transitions; Singh et al, 2021), are sensitive to isoleucine might reveal how the parasites' time-keeping mechanism operates. Whilst by no means conclusive, our results feed the debate about whether malaria parasites keep time by an endogenous circadian oscillator or a simpler mechanism.…”

Section: Biogenic Amines and Amino Acidsmentioning

confidence: 99%

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

Prior¹,

Middleton²,

Owolabi³

et al. 2021

Wellcome Open Res

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Background: Rapid asexual replication of blood stage malaria parasites is responsible for the severity of disease symptoms and fuels the production of transmission forms. Here, we demonstrate that the Plasmodium chabaudi’s schedule for asexual replication can be orchestrated by isoleucine, a metabolite provided to the parasite in periodic manner due to the host’s rhythmic intake of food. Methods: We infect female C57BL/6 and Per1/2-null TTFL clock-disrupted mice with 1×105 red blood cells containing P. chabaudi (DK genotype). We perturb the timing of rhythms in asexual replication and host feeding-fasting cycles to identify nutrients with rhythms that match all combinations of host and parasite rhythms. We then test whether perturbing the availability of the best candidate nutrient in vitro elicits changes their schedule for asexual development. Results: Our large-scale metabolomics experiment and follow up experiments reveal that only one metabolite - the amino acid isoleucine – fits criteria for a time-of-day cue used by parasites to set the schedule for replication. The response to isoleucine is a parasite strategy rather than solely the consequences of a constraint imposed by host rhythms, because unlike when parasites are deprived of other essential nutrients, they suffer no apparent costs from isoleucine withdrawal. Conclusions: Overall, our data suggest parasites can use the daily rhythmicity of blood-isoleucine concentration to synchronise asexual development with the availability of isoleucine, and potentially other resources, that arrive in the blood in a periodic manner due to the host’s daily feeding-fasting cycle. Identifying both how and why parasites keep time opens avenues for interventions; interfering with the parasite’s time-keeping mechanism may stall replication, increasing the efficacy of drugs and immune responses, and could also prevent parasites from entering dormancy to tolerate drugs.

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“…SR10 is a likely candidate for modulating IDC duration in response to perturbations of host time-of-day (Subudhi et al 2020) and a parasite stage early in the IDC is likely responsible for time-keeping (McLean and Jacobs-Lorena 2020). Identifying KIN (Mancio-Silva et al 2017), regulated pathways and those associated with other genes recently suggested to impact the IDC schedule, including SR10 (Subhudi et al 2020), and PK7/MORC (Singh et al 2021), and determining whether they are sensitive to isoleucine might reveal how the parasites’ timekeeping mechanism operates. It is also possible that parasites keep time with an endogenous clock (Reece et al 2017, Prior et al 2020).…”

Section: Discussionmentioning

confidence: 99%

“…To date, the only candidate player identified is SR10, which modulates IDC duration in response to perturbations of host time-of-day (Subudhi et al 2020). Identifying KIN (Mancio-Silva et al 2017), regulated pathways whether they, along with pathways associated with SR10 (Subhudi et al 2020), and PK7/MORC (which is involved in IDC stage transitions; Singh et al 2021), are sensitive to isoleucine might reveal how the parasites’ time-keeping mechanism operates. Whilst by no means conclusive, our results feed the debate about whether malaria parasites possess an endogenous circadian clock.…”

Section: Discussionmentioning

confidence: 99%

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

Prior

Middleton

Owolabi

et al. 2020

Preprint

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The replication of blood-stage malaria parasites is synchronised to the host’s daily feeding rhythm. We demonstrate that a metabolite provided to the parasite from the host’s food can set the schedule for Plasmodium chabaudi’s intraerythrocytic development cycle (IDC). First, a large-scale screen reveals multiple rhythmic metabolites in the blood that match the timing of the IDC, but only one - the amino acid isoleucine - that malaria parasites must scavenge from host food. Second, perturbing the timing of isoleucine provision and withdrawal demonstrate that parasites use isoleucine to schedule and synchronise their replication. Thus, periodicity in the concentration of isoleucine in the blood, driven by host-feeding rhythms, explains why timing is beneficial to the parasite and how it coordinates with host rhythms. Blood-stage replication of malaria parasites is responsible for the severity of disease symptoms and fuels transmission; disrupting metabolite-sensing by parasites offers a novel intervention to reduce parasite fitness.

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A nuclear protein, PfMORC confers melatonin dependent synchrony of the human malaria parasite P. falciparum in the asexual stage

Cited by 19 publications

References 53 publications

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

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

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

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

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