Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid.
| Autor: | Prior KF; Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK.; Institute of Immunology & Infection Research, University of Edinburgh, Edinburgh, UK., Middleton B; School of Biosciences and Medicine, University of Surrey, Surrey, UK., Owolabi ATY; Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK.; Institute of Immunology & Infection Research, University of Edinburgh, Edinburgh, UK., Westwood ML; Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK.; Institute of Immunology & Infection Research, University of Edinburgh, Edinburgh, UK., Holland J; Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK.; Institute of Immunology & Infection Research, University of Edinburgh, Edinburgh, UK., O'Donnell AJ; Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK.; Institute of Immunology & Infection Research, University of Edinburgh, Edinburgh, UK., Blackman MJ; Malaria Biochemistry Laboratory, Francis Crick Institute, London, UK.; Faculty of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK., Skene DJ; School of Biosciences and Medicine, University of Surrey, Surrey, UK., Reece SE; Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK.; Institute of Immunology & Infection Research, University of Edinburgh, Edinburgh, UK. |
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| Jazyk: | angličtina |
| Zdroj: | Wellcome open research [Wellcome Open Res] 2021 Oct 20; Vol. 6, pp. 186. Date of Electronic Publication: 2021 Oct 20 (Print Publication: 2021). |
| DOI: | 10.12688/wellcomeopenres.16894.2 |
| Abstrakt: | 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 1×10 5 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. Competing Interests: No competing interests were disclosed. (Copyright: © 2021 Prior KF et al.) |
| Databáze: | MEDLINE |
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