title: Evolutionary ecology of daily rhythms in malaria parasites
title: The evolutionary ecology of daily rhythms in malaria parasites
titleType: AlternativeTitle
Creators: name: Owolabi, Alíz T. Y.
Publisher: name: The University of Edinburgh
Year: 2023
Subjects: Circadian rhythms
malaria parasites
parasites’ replication rhythm
variable synchrony
mouse model
drug efficacy

description: Circadian rhythms are (approximately) 24-hour oscillations in biological processes such as gene expression, physiology, and behaviour, which allow organisms to schedule their activities around the predictable environmental changes caused by the Earth’s daily rotation. Being in tune with the environment confers an adaptive advantage to organisms across diverse taxa. Moreover, daily rhythms are important for interactions between hosts and pathogens, and shape infection dynamics in a variety of natural systems. Daily rhythms are a hallmark of malaria infections, in which single-celled Plasmodium parasites replicate in vertebrate hosts’ blood by cyclically invading red blood cells (RBCs), multiplying, and eventual RBC bursting. This bursting often occurs synchronously, at 24- 48- or 72-hour intervals, depending on the parasite species. Asexual parasites progress through this intra-erythrocytic developmental cycle (IDC) as three consecutive developmental stages (ring, trophozoite, schizont), and in each IDC a small but variable proportion of parasites form sexual transmission stages (gametocytes), which are infectious to the mosquito vector. The IDC is responsible for many of the disease symptoms in malaria and asexual replication fuels transmission potential by boosting parasite density in the blood. The timing of RBC bursting is set by the host’s feeding-fasting rhythm – parasites burst during hosts’ feeding time – but this coordination can be misaligned. When parasites are misaligned with the host’s rhythm, they experience fitness costs, which suggests IDC rhythms are important to parasites and may be a target for intervention. Moreover, synchrony in replication varies between and within infections, and some Plasmodium species replicate asynchronously but the selective pressures that lead to the evolution of different replication rhythms, and the costs and benefits of (un)coordinated replication are unclear. In my thesis, I use an evolutionary-ecological framework to investigate the costs and benefits of synchrony, and how daily rhythms in replication and alignment with host rhythms interact with virulence and drug efficacy in a murine model system using the synchronous species Plasmodium chabaudi. In Chapter 1, I ask if synchronous replication is costly or beneficial for parasites and hosts, and if this is dependent on host daily rhythms. I compare parasite fitness proxies in synchronous and asynchronous infections in rhythmic and arrhythmic hosts, and the impacts on host health. I show that, surprisingly, asynchronous development in the blood could be advantageous to parasites, as gametocytes are more abundant in asynchronous infections. Harbouring synchronous infections takes moderately higher toll on hosts’ health, disproportionately lowering blood glucose concentration and disrupting body temperature more severely than asynchronous infections. My findings also indicate that infecting rhythmic hosts confers both costs and benefits to parasites, in the form of lower asexual but higher sexual parasite densities. Additionally, host rhythmicity phenotype has conflicting consequences for the hosts themselves, as rhythmic hosts lose less of their blood glucose but more of their RBCs, and their locomotor rhythms are more disrupted than for arrhythmic hosts. In Chapter 2, inspired by previous research that suggests more virulent parasites cope better with a variety of challenges in the within-host environment, I investigate whether virulent genotypes are less affected by host-parasite temporal misalignment than avirulent genotypes. I also test the prediction that virulent parasites, which reach a high density and deplete more host RBCs, exhibit dampened synchrony to avoid costs of crowding. I compare two genetically related parasite clones – one significantly more virulent than the other – in infections aligned or misaligned to host rhythms. My results demonstrate that virulent parasites are indeed less synchronous and have the potential to recover more rapidly from misalignment compared to their avirulent counterparts. This warns that virulent genotypes could compensate more readily against any future intervention strategies aimed at disrupting parasite rhythms. Lastly, in Chapter 3 I focus on how the IDC rhythm affects drug-based interventions. I examine drug efficacy of the front-line antimalarial artemisinin when treating younger (rings) versus older parasite stages (trophozoites). To separate the potential impacts of IDC stage and host time of day, I treat each parasite stage at several different times of day – in aligned and misaligned infections. I find that trophozoites are more sensitive to artemisinin than rings and that although host rhythms per se do not have a direct effect, uncoupling host and parasite rhythms exacerbates the stage-specificity in drug efficacy. These data reveal that parasite sensitivity to drugs may be enhanced (for trophozoites) or attenuated (for rings) by perturbing the IDC’s timing in relation to the host. The research in my thesis helps identify novel ways to target malaria parasites, demonstrates how they might recover from perturbations and more broadly, contributes to growing efforts to determine how rhythmicity impacts infection dynamics, disease severity, intervention success and evolutionary trajectories in host-parasite interactions.