Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid [version 2; peer review: 2 approved]

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 metabolit...

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Autores principales:	Kimberley F. Prior, Benita Middleton, Alíz T.Y. Owolabi, Mary L. Westwood, Jacob Holland, Aidan J. O'Donnell, Michael J. Blackman, Debra J. Skene, Sarah E. Reece
Formato:	article
Lenguaje:	EN
Publicado:	Wellcome 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/15e9db7e34144d7dac9cd75b576f119d
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spelling	oai:doaj.org-article:15e9db7e34144d7dac9cd75b576f119d2021-11-15T15:27:33ZSynchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid [version 2; peer review: 2 approved]2398-502X10.12688/wellcomeopenres.16894.2https://doaj.org/article/15e9db7e34144d7dac9cd75b576f119d2021-10-01T00:00:00Zhttps://wellcomeopenresearch.org/articles/6-186/v2https://doaj.org/toc/2398-502XBackground: 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.Kimberley F. PriorBenita MiddletonAlíz T.Y. OwolabiMary L. WestwoodJacob HollandAidan J. O'DonnellMichael J. BlackmanDebra J. SkeneSarah E. ReeceWellcomearticleMedicineRScienceQENWellcome Open Research, Vol 6 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kimberley F. Prior Benita Middleton Alíz T.Y. Owolabi Mary L. Westwood Jacob Holland Aidan J. O'Donnell Michael J. Blackman Debra J. Skene Sarah E. Reece Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid [version 2; peer review: 2 approved]
description	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.
format	article
author	Kimberley F. Prior Benita Middleton Alíz T.Y. Owolabi Mary L. Westwood Jacob Holland Aidan J. O'Donnell Michael J. Blackman Debra J. Skene Sarah E. Reece
author_facet	Kimberley F. Prior Benita Middleton Alíz T.Y. Owolabi Mary L. Westwood Jacob Holland Aidan J. O'Donnell Michael J. Blackman Debra J. Skene Sarah E. Reece
author_sort	Kimberley F. Prior
title	Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid [version 2; peer review: 2 approved]
title_short	Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid [version 2; peer review: 2 approved]
title_full	Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid [version 2; peer review: 2 approved]
title_fullStr	Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid [version 2; peer review: 2 approved]
title_full_unstemmed	Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid [version 2; peer review: 2 approved]
title_sort	synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid [version 2; peer review: 2 approved]
publisher	Wellcome
publishDate	2021
url	https://doaj.org/article/15e9db7e34144d7dac9cd75b576f119d
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Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid [version 2; peer review: 2 approved]

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