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dc.contributor.advisorReece, Sarah
dc.contributor.advisorSchneider, Petra
dc.contributor.authorO’Donnell, Aidan J.
dc.date.accessioned2022-04-12T12:25:15Z
dc.date.available2022-04-12T12:25:15Z
dc.date.issued2022-04-11
dc.identifier.urihttps://hdl.handle.net/1842/38866
dc.identifier.urihttp://dx.doi.org/10.7488/era/2120
dc.description.abstractBiological rhythms are a ubiquitous feature of life and are assumed to allow organisms coordinate their activities with daily rhythms in the abiotic environment resulting from the rotation of the Earth every 24 hours. The genes and molecular mechanisms underpinning circadian clocks in multicellular organisms are relatively well understood in contrast to the evolution and ecology of circadian rhythms. Circadian rhythms mediate interactions between organisms; from predators and prey, to mating behaviours between males and females, to hosts and parasites. The role of daily rhythms in infections is gaining traction because explaining the regulatory mechanisms and fitness consequences of biological rhythms exhibited by parasites and hosts offers new avenues to treat infections. Here, I explore how periodicity in parasite traits is generated and why daily rhythms matter for parasite fitness. My work focuses on malaria (Plasmodium) parasites which exhibit developmental rhythms during replication in the mammalian host’s blood and during transmission to insect vectors. Rhythmic in-host parasite replication is responsible for eliciting inflammatory responses, severe anaemia, fuels transmission, and can confer tolerance to anti-parasite drugs. Thus, understanding both how and why the timing and synchrony of parasites are connected to the daily rhythms of hosts and vectors may make treatment more effective and less toxic to hosts. My papers integrate an evolutionary ecology approach with chronobiology and parasitology to investigate how host-parasite-vector interactions shape the evolution of rhythmicity in parasites traits. I have used a rodent malaria parasite model system (Plasmodium chabaudi) for my experiments, capitalising on the tractability of this model for the human malaria, P. falciparum. P. chabaudi exhibits a 24-hour rhythm in replication, facilitates ecologically realistic studies because experiments can be carried out in vivo (compared to the in vitro limitations on studying human parasites), and perturbations to the timing of the in-host and in-vector environments are straightforward. My findings include: 1) Perturbing the timing of parasite rhythms with respect to the timing of host rhythms (analogous to giving the parasites “jet lag”), results in a fitness cost to the parasites, evident by a 50% reduction in both asexually replicating and transmission stage parasites. 2) The consequences of temporal mismatch to the host manifest very early in the infection (within 48 hours, i.e. the first 1-2 cycles of replication) and are dependent on the parasite stage by which infections are initiated (0-12 hour old parasites suffer a cost, whereas 12-24 hour parasites benefit). 3) The timing of the parasite replication cycle is independent of the canonical ‘core’ host clock (i.e. transcription translation feedback loop) and instead depends on the timing of feeding-fasting rhythms of the host. 4) If perturbed, the timing of the parasite’s rhythm reschedules to regain synchrony with the timing of the host’s rhythm within 7 replication cycles. Specifically, parasites achieve this by speeding up the replication rhythm by 2-3 hours per cycle, and the rate of rescheduling is independent of parasite density. 5) Naturally asynchronous Plasmodium species are ‘resistant’ to conditions that lead to alignment with host rhythms in synchronously replicating species. This suggests that unknown ecological differences between these parasite species selects for vastly different schedules of within-host replication rather than some species being constrained to replicate asynchronously. 6) In addition to the timing of parasite rhythms impacting directly upon within-host dynamics, timing also matters – albeit indirectly - for transmission, via impacts on the population dynamics of the vector. For example, receiving a blood meal in the morning makes mosquitoes more likely to lay eggs, lay slightly sooner and have a larger clutch size than those feeding at night. Yet, whilst mosquitoes infected with malaria die sooner, the effects of taking a blood meal at different times of day do not impact transmission of an asynchronously replicating malaria parasite. It is beneficial for parasites to be in synchronization with their host’s feeding-fasting rhythms and plasticity in the IDC duration facilitates this synchrony by enabling parasites to make small daily changes to their IDC schedule when necessary. Understanding the extent of, and limits on, plasticity in the IDC schedule is important as it may reveal targets for novel interventions, such as drugs to disrupt IDC regulation and preventing IDC dormancy conferring tolerance to existing drugs. More generally, our results provide a demonstration of the adaptive value of biological rhythms and the utility of using an evolutionary framework to understand parasite traits.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionO'Donnell A. J., Schneider P., McWatters H. G. and Reece S. E. (2011). "Fitness costs of disrupting circadian rhythms in malaria parasites." Proceedings of the Royal Society B: Biological Sciences 278: 2429 - 2436en
dc.relation.hasversionO'Donnell, A. J., Mideo N. and Reece S. E. (2013). "Disrupting rhythms in Plasmodium chabaudi: costs accrue quickly and independently of how infections are initiated." Malaria Journal 12: 372.en
dc.relation.hasversionO'Donnell, A. J., Mideo N. and Reece S. E. (2014). "Correction: disrupting rhythms in Plasmodium chabaudi: costs accrue quickly and independently of how infections are initiated." Malaria Journal 13(1): 503en
dc.relation.hasversionO’Donnell, A. J., Rund S. S. C. and Reece S. E. (2019). "Time-of-day of blood-feeding: effects on mosquito life history and malaria transmission." Parasites & vectors 12(1): 1-16en
dc.relation.hasversionO'Donnell, A. J., Prior K. F. and Reece S. E. (2020). "Host circadian clocks do not set the schedule for the within-host replication of malaria parasites." Proceedings of the Royal Society B: Biological Sciences 287(1932): 20200347en
dc.relation.hasversionO’Donnell, A. J. and Reece S. E. (2021a). "Ecology of asynchronous asexual replication: the intraerythrocytic development cycle of Plasmodium berghei is resistant to host rhythms." Malaria Journal 20(1): 1-12.en
dc.relation.hasversionO’Donnell, A. J., Greischar M.A. & Reece S. E. (2021b). "Mistimed malaria parasites re synchronise with host feeding-fasting rhythms by shortening the duration of intra-erythrocytic development." Parasite Immunology e12898en
dc.subjectcircadianen
dc.subjectplasmodiumen
dc.subjectecologyen
dc.subjectrhythmsen
dc.subjectparasiteen
dc.subjectmalariaen
dc.titleEvolutionary ecology of biological rhythms in malaria parasitesen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD(P) Doctor of Philosophy by Research Publicationsen


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