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• W4256305813 abstract "<ns4:p><ns4:bold>Background: </ns4:bold>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 <ns4:italic>Plasmodium chabaudi’s</ns4:italic> 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.</ns4:p><ns4:p> <ns4:bold>Methods: </ns4:bold>We infect female C57BL/6 and Per1/2-null mice which have a disrupted canonical (transcription translation feedback loop, TTFL) clock with 1×10<ns4:sup>5</ns4:sup> red blood cells containing <ns4:italic>P. chabaudi</ns4:italic> (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 <ns4:italic>in vitro</ns4:italic> changes the schedule for asexual development.</ns4:p><ns4:p> <ns4:bold>Results: </ns4:bold>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.</ns4:p><ns4:p> <ns4:bold>Conclusions: </ns4:bold>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.</ns4:p>" @default.
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• W4256305813 date "2021-10-20" @default.
• W4256305813 modified "2023-09-28" @default.
• W4256305813 title "Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid" @default.
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• W4256305813 doi "https://doi.org/10.12688/wellcomeopenres.16894.2" @default.
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