Abstract
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.
Highlights
Circadian rhythms are assumed to have evolved to coordinate organisms’ activities with daily rhythms in the environment (Hozer et al, 2020; Ouyang et al, 1998; Spoelstra et al, 2016)
Metabolites that associate with host feeding rhythms and the intraerythrocytic development cycle (IDC) schedule To identify metabolites whose rhythms correspond to the timing of host feeding and the IDC schedule, we compared four groups of malaria infections in mice that were either wild type (WT) C57BL/6J strain or Per1/2-null (Period 1 and Period 2) circadian clock-disrupted mice
Assuming P. chabaudi has analogous mechanisms, we propose that elevated isoleucine is used by the parasite as a marker for a sufficiently nutrient-rich environment to traverse cell cycle checkpoints and complete the IDC (McLean & Jacobs-Lorena, 2020; O’Neill et al, 2020)
Summary
Circadian rhythms are assumed to have evolved to coordinate organisms’ activities with daily rhythms in the environment (Hozer et al, 2020; Ouyang et al, 1998; Spoelstra et al, 2016). Some host rhythms offer opportunities for parasites to exploit, whilst other rhythms impose constraints parasites must cope with. Some parasites use their own circadian clocks to control metabolism (Rijo-Ferreira et al, 2017), and virulence (Hevia et al, 2015), suggesting that host rhythms are a selective (evolutionary) driver of parasite rhythms. Host rhythms have fitness consequences for malaria (Plasmodium) parasites (O’Donnell et al, 2011; O’Donnell et al, 2013), whose rhythmicity in development during blood-stage replication is aligned with the timing of host feeding-fasting cycles (Hirako et al, 2018; O’Donnell et al, 2020; Prior et al, 2018). 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. 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 version 2 (revision)
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