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• W3005983517 abstract "Biological rhythms appear to be an elegant solution to the challenge of coordinating activities with the consequences of the Earth’s daily and seasonal rotation. The genes and molecular mechanisms underpinning circadian clocks in multicellular organisms are well understood. In contrast, the regulatory mechanisms and fitness consequences of biological rhythms exhibited by parasites remain mysterious. Here, we explore how periodicity in parasite traits is generated and why daily rhythms matter for parasite fitness. We focus on malaria (Plasmodium) parasites which exhibit developmental rhythms during replication in the mammalian host’s blood and in transmission to vectors. Rhythmic in-host parasite replication is responsible for eliciting inflammatory responses, the severity of disease symptoms, and fueling transmission, as well as conferring 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. Biological rhythms appear to be an elegant solution to the challenge of coordinating activities with the consequences of the Earth’s daily and seasonal rotation. The genes and molecular mechanisms underpinning circadian clocks in multicellular organisms are well understood. In contrast, the regulatory mechanisms and fitness consequences of biological rhythms exhibited by parasites remain mysterious. Here, we explore how periodicity in parasite traits is generated and why daily rhythms matter for parasite fitness. We focus on malaria (Plasmodium) parasites which exhibit developmental rhythms during replication in the mammalian host’s blood and in transmission to vectors. Rhythmic in-host parasite replication is responsible for eliciting inflammatory responses, the severity of disease symptoms, and fueling transmission, as well as conferring 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. Malaria infections are frequently lethal, especially in children under 5 years of age, and 40% of the world’s population lives in endemic areas (World Malaria Report 2019https://www.who.int/publications-detail/world-malaria-report-2019Date: 2019Google Scholar). Fever rhythms during malaria infection were first documented during the Hippocratic era, and later, the interval (periodicity) between fever bouts were used to diagnose the species of Plasmodium a patient was infected with. Fever is a direct consequence of the inflammatory response that is elicited when a cohort of asexually replicating stages synchronously burst out of the host’s red blood cells (schizogony) to release their progeny (merozoites). Following release, merozoites invade more red blood cells (RBCs) to initiate a new cycle of asexual replication termed the “intra-erythrocytic development cycle” (IDC; Figures 1A and 1B ; Gerald et al., 2011Gerald N. Mahajan B. Kumar S. Mitosis in the human malaria parasite Plasmodium falciparum.Eukaryot. Cell. 2011; 10: 474-482Crossref PubMed Scopus (82) Google Scholar). Within every cycle, a small proportion of parasites commit to differentiating into sexual stages (termed “gametocytes”), which are responsible for infecting insect vectors. Upon being taken up in a mosquito vector’s blood meal, gametocytes rapidly differentiate into gametes and then mate. The offspring undergo extensive replication before eventually making their way to the salivary glands to be transmitted to new hosts. The IDCs of most species of Plasmodium last for multiples of 24 h (Mideo et al., 2013Mideo N. Reece S.E. Smith A.L. Metcalf C.J.E. The Cinderella syndrome: why do malaria-infected cells burst at midnight?.Trends Parasitol. 2013; 29: 10-16Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar), suggesting a circadian basis. A flurry of interest several decades ago (stimulated by Hawking et al., 1968Hawking F. Worms M.J. Gammage K. Host temperature and control of 24-hour and 48-hour cycles in malaria parasites.Lancet. 1968; 1: 506-509Abstract PubMed Google Scholar, Hawking, 1970Hawking F. The clock of the malaria parasite.Sci. Am. 1970; 222: 123-131Crossref PubMed Scopus (27) Google Scholar) proposed explanations for the rhythmicity observed in development during the IDC, but these hypotheses have proved hard to reconcile with recent observations. A better understanding of how the IDC schedule is controlled in vivo (Figure 1B) is necessary for several reasons. First, asexual replication underpins the severe symptoms of malaria infection (Gazzinelli et al., 2014Gazzinelli R.T. Kalantari P. Fitzgerald K.A. Golenbock D.T. Innate sensing of malaria parasites.Nat. Rev. Immunol. 2014; 14: 744-757Crossref PubMed Scopus (149) Google Scholar) and fuels the production of gametocytes (Carter et al., 2013Carter L.M. Kafsack B.F.C. Llinás M. Mideo N. Pollitt L.C. Reece S.E. Stress and sex in malaria parasites: Why does commitment vary?.Evol. Med. Public Health. 2013; 2013: 135-147Crossref PubMed Google Scholar). Second, tolerance to antimalarial medications involves a period of dormancy during the IDC (Teuscher et al., 2010Teuscher F. Gatton M.L. Chen N. Peters J. Kyle D.E. Cheng Q. Artemisinin-induced dormancy in plasmodium falciparum: duration, recovery rates, and implications in treatment failure.J. Infect. Dis. 2010; 202: 1362-1368Crossref PubMed Scopus (145) Google Scholar), suggesting plasticity in the IDC can be employed as a survival strategy. Third, reports of malaria-vectoring mosquitoes evading bed nets by altering the time of day they forage for blood suggests the temporal selective landscape of malaria parasites is changing (Thomsen et al., 2017Thomsen E.K. Koimbu G. Pulford J. Jamea-Maiasa S. Ura Y. Keven J.B. Siba P.M. Mueller I. Hetzel M.W. Reimer L.J. Mosquito behavior change after distribution of bednets results in decreased protection against malaria exposure.J. Infect. Dis. 2017; 215: 790-797PubMed Google Scholar). Having an IDC that is coordinated to the host’s circadian rhythm matters for parasite fitness (O’Donnell et al., 2011O’Donnell A.J. Schneider P. McWatters H.G. Reece S.E. Fitness costs of disrupting circadian rhythms in malaria parasites.Proc. Biol. Sci. 2011; 278: 2429-2436Crossref PubMed Scopus (66) Google Scholar, O’Donnell et al., 2013O’Donnell A.J. Mideo N. Reece S.E. Disrupting rhythms in Plasmodium chabaudi: costs accrue quickly and independently of how infections are initiated.Malar. J. 2013; 12: 372Crossref PubMed Scopus (22) Google Scholar). However, why the parasites benefit from their IDC schedule and how the IDC schedule is controlled remain mysterious. Here, we outline how the integration of parasitology with chronobiology, evolutionary ecology, and immunology is uncovering how the IDC is scheduled and what its fitness consequences are for malaria parasites. Recent work has begun to understand how the daily rhythms exhibited by hosts and vectors impose challenges that parasites must cope with and, conversely, offer opportunities that parasites can exploit. We focus on Plasmodium spp. (malaria parasites) because their rhythms are the best understood, and draw inferences from other parasites where relevant. Recognizing that daily rhythms underpin infection processes could reveal times of day that parasites are particularly vulnerable to drug treatment, when drugs are least toxic, and how the host’s rhythms might be harnessed to improve defense and recovery. We introduce the relevant concepts from chronobiology and evolutionary ecology, evaluate whether malaria parasites can keep time, then consider how the daily rhythms of hosts and vectors generate a highly dynamic and complex environment for parasites to navigate, before highlighting the major areas for future work. Like almost all organisms, parasites experience a rhythmic world (Reece et al., 2017Reece S.E. Prior K.F. Mideo N. The life and times of parasites: rhythms in strategies for within-host survival and between-host transmission.J. Biol. Rhythms. 2017; 32: 516-533Crossref PubMed Scopus (26) Google Scholar, Rijo-Ferreira et al., 2017aRijo-Ferreira F. Takahashi J.S. Figueiredo L.M. Circadian rhythms in parasites.PLoS Pathog. 2017; 13: e1006590Crossref PubMed Scopus (13) Google Scholar, Westwood et al., 2019Westwood M.L. O’Donnell A.J. de Bekker C. Lively C.M. Zuk M. Reece S.E. The evolutionary ecology of circadian rhythms in infection.Nat. Ecol. Evol. 2019; 3: 552-560Crossref PubMed Scopus (23) Google Scholar). While inside vertebrate hosts, parasites are somewhat sheltered from rhythms in the “abiotic” external environment thanks to the homeostasis of the host. However, within the host, they are confronted with a myriad of daily “biotic” rhythms in behaviors, physiologies, and cellular processes driven by the circadian clocks of their host (Figure 1; Pittendrigh, 1960Pittendrigh C.S. Circadian rhythms and the circadian organization of living systems.Cold Spring Harb. Symp. Quant. Biol. 1960; 25: 159-184Crossref PubMed Scopus (802) Google Scholar, Reece et al., 2017Reece S.E. Prior K.F. Mideo N. The life and times of parasites: rhythms in strategies for within-host survival and between-host transmission.J. Biol. Rhythms. 2017; 32: 516-533Crossref PubMed Scopus (26) Google Scholar). For example, rhythms in immune defenses may make it dangerous for parasites to perform certain activities at a particular time of day, and rhythms in host foraging may result in resources only being abundant at certain times of day. While it is not clear why malaria parasites exhibit a rhythmic IDC (a Plasmodium clock has yet to be discovered), their hosts and vectors benefit from using circadian clocks to govern many behaviors and physiologies. Organisms are thought to garner fitness benefits from coordinating with rhythms in the external environment (“extrinsic adaptive value”) and from temporally compartmentalizing incompatible physiological or cellular processes (“intrinsic adaptive value”; Sharma, 2003Sharma V.K. Adaptive significance of circadian clocks.Chronobiol. Int. 2003; 20: 901-919Crossref PubMed Scopus (126) Google Scholar). For example, experiments using cyanobacteria and Arabidopsis reveal that rhythms matching the duration of the light-dark cycle provide an advantage over competitors whose rhythms have a different duration (Ouyang et al., 1998Ouyang Y. Andersson C.R. Kondo T. Golden S.S. Johnson C.H. Resonating circadian clocks enhance fitness in cyanobacteria.Proc. Natl. Acad. Sci. USA. 1998; 95: 8660-8664Crossref PubMed Scopus (521) Google Scholar, Dodd et al., 2005Dodd A.N. Salathia N. Hall A. Kévei E. Tóth R. Nagy F. Hibberd J.M. Millar A.J. Webb A.A.R. Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage.Science. 2005; 309: 630-633Crossref PubMed Scopus (932) Google Scholar). Most of the daily rhythms exhibited by mammalian hosts and insect vectors are driven by circadian clocks. Across disparate species, the canonical clock mechanism shares a similar design (Figure 2A), but the specific genes and proteins involved are distinct (Dunlap, 1999Dunlap J.C. Molecular bases for circadian clocks.Cell. 1999; 96: 271-290Abstract Full Text Full Text PDF PubMed Scopus (2205) Google Scholar). The common feature across different taxa is the presence of a self-sustaining transcription-translation feedback loop (TTFL), operative within individual cells. For instance, in mammals, heterodimers of basic helix-loop-helix transcription factors produce transcriptional activation of target genes, which include the Period (Per1-Per3) and Cryptochrome (Cry1- Cry2) genes. Protein products to the Per and Cry genes feed back to repress their own expression, providing a molecular feedback loop with a cycle length of approximately 24 h (Figures 2A and 2B; Reppert and Weaver, 2002Reppert S.M. Weaver D.R. Coordination of circadian timing in mammals.Nature. 2002; 418: 935-941Crossref PubMed Scopus (3112) Google Scholar). An interlocking feedback loop of additional transcription factors stabilizes and enhances the core clock loop. Chromatin remodeling enzymes, other transcription factors, and proteins affect the activity and stability of these core clock proteins (including casein kinases, protein phosphatases, and several F-box proteins), influencing cycle length and gene expression rhythms (Takahashi, 2015Takahashi J.S. Molecular components of the circadian clock in mammals.Diabetes Obes. Metab. 2015; 17: 6-11Crossref PubMed Scopus (115) Google Scholar). Additional levels of regulation abound, with post-transcriptional and post-translational regulatory mechanisms now well established (Koike et al., 2012Koike N. Yoo S.H. Huang H.C. Kumar V. Lee C. Kim T.K. Takahashi J.S. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals.Science. 2012; 338: 349-354Crossref PubMed Scopus (801) Google Scholar, Kojima and Green, 2015Kojima S. Green C.B. Circadian genomics reveal a role for post-transcriptional regulation in mammals.Biochemistry. 2015; 54: 124-133Crossref PubMed Scopus (33) Google Scholar). Studies in mouse tissues reveal that as many as 40% of genes are rhythmically expressed in at least one tissue (Zhang et al., 2014Zhang R. Lahens N.F. Ballance H.I. Hughes M.E. Hogenesch J.B. A circadian gene expression atlas in mammals: implications for biology and medicine.Proc. Natl. Acad. Sci. USA. 2014; 111: 16219-16224Crossref PubMed Scopus (951) Google Scholar). The expression of circadian clock-regulated genes exhibits periods (durations) of ∼24 h, and their phase and amplitude serve as useful parameters to compare rhythms across experimental groups (Figure 2B). Circadian clocks are also temperature compensated, enabling them to tick at the correct pace across a biologically relevant temperature gradient (Figure 2C). Clock-regulated genes often include key, rate-limiting steps in biological and metabolic processes (Panda et al., 2002Panda S. Antoch M.P. Miller B.H. Su A.I. Schook A.B. Straume M. Schultz P.G. Kay S.A. Takahashi J.S. Hogenesch J.B. Coordinated transcription of key pathways in the mouse by the circadian clock.Cell. 2002; 109: 307-320Abstract Full Text Full Text PDF PubMed Scopus (1755) Google Scholar) and include many targets for top-selling pharmaceutics (Zhang et al., 2014Zhang R. Lahens N.F. Ballance H.I. Hughes M.E. Hogenesch J.B. A circadian gene expression atlas in mammals: implications for biology and medicine.Proc. Natl. Acad. Sci. USA. 2014; 111: 16219-16224Crossref PubMed Scopus (951) Google Scholar, Ruben et al., 2018Ruben M.D. Wu G. Smith D.F. Schmidt R.E. Francey L.J. Lee Y.Y. Anafi R.C. Hogenesch J.B. A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine.Sci. Transl. Med. 2018; 10https://doi.org/10.1126/scitranslmed.aat8806Crossref PubMed Scopus (75) Google Scholar). The mammalian circadian clock thus casts a pervasive influence on the function of numerous cell types and tissues, including important effects on metabolism (Bass, 2012Bass J. Circadian topology of metabolism.Nature. 2012; 491: 348-356Crossref PubMed Scopus (415) Google Scholar, Sancar and Brunner, 2014Sancar G. Brunner M. Circadian clocks and energy metabolism.Cell. Mol. Life Sci. 2014; 71: 2667-2680Crossref PubMed Scopus (40) Google Scholar, Rijo-Ferreira and Takahashi, 2019Rijo-Ferreira F. Takahashi J.S. Genomics of circadian rhythms in health and disease.Genome Med. 2019; 11: 82Crossref PubMed Scopus (64) Google Scholar). Mechanisms for circadian rhythmicity also exist that are not dependent upon the known TTFL genes and mechanisms. Biochemical (redox) rhythms in human erythrocytes occur in vitro despite the absence of transcription (O’Neill and Reddy, 2011O’Neill J.S. Reddy A.B. Circadian clocks in human red blood cells.Nature. 2011; 469: 498-503Crossref PubMed Scopus (526) Google Scholar). These redox rhythms are thought to be mediated by rhythmic ion transport (Feeney et al., 2016Feeney K.A. Hansen L.L. Putker M. Olivares-Yañez C. Day J. Eades L.J. Larrondo L.F. Hoyle N.P. O’Neill J.S. van Ooijen G. Daily magnesium fluxes regulate cellular timekeeping and energy balance.Nature. 2016; 532: 375-379Crossref PubMed Scopus (110) Google Scholar; Henslee et al., 2017Henslee E.A. Crosby P. Kitcatt S.J. Parry J.S.W. Bernardini A. Abdallat R.G. Braun G. Fatoyinbo H.O. Harrison E.J. Edgar R.S. et al.Rhythmic potassium transport regulates the circadian clock in human red blood cells.Nat. Commun. 2017; 8: 1978Crossref PubMed Scopus (28) Google Scholar) and are evolutionarily ancient (Edgar et al., 2012Edgar R.S. Green E.W. Zhao Y. van Ooijen G. Olmedo M. Qin X. Xu Y. Pan M. Valekunja U.K. Feeney K.A. et al.Peroxiredoxins are conserved markers of circadian rhythms.Nature. 2012; 485: 459-464Crossref PubMed Scopus (531) Google Scholar). Precisely how different types of clock interact, and how clocks situated in different organs throughout an organism are coordinated, are unclear. In mammals, TTFL clocks situated in the suprachiasmatic nucleus of the brain (the SCN, also known as the central or “master” clock) relay light-dark cycle information to peripheral clocks, and peripheral clocks also schedule (“entrain”) to other rhythmic events such as feeding (Figure 2D). Thus, the daily rhythms of hosts (and vectors) generate a highly dynamic and complex environment for parasites to navigate. In the context of explaining how host-parasite interactions shape the IDC, most work focuses on identifying the genes or molecular pathways that determine IDC progression. Here, we advocate including an evolutionary ecology framework. This framework considers how interactions (both within and between species, and with aspects of the environment) shape the traits exhibited by organisms through adaptation and selection. Coevolution recognizes that the consequences of evolutionary change to a parasite trait may impose selection on host and vector traits, and vice-versa. In the context of this paper, evolutionary ecology poses the questions “to what extent, and why, is natural selection acting on parasites, hosts, and vectors responsible for shaping the IDC schedule” (Figure 3)? Answering these questions involves deconstructing the IDC into quantitative traits that natural selection could act on and asking how parasite ecology affects the costs and benefits garnered from different values that IDC traits could plausibly take. Put another way, could the IDC exhibit different timing and degrees of synchrony (trait values)? If so, is the observed IDC schedule the one that returns the highest possible fitness in terms of within-host survival and between-host transmission? If not, why don’t parasites exhibit the “best” IDC schedule? Furthermore, if there is variation between genotypes (or species) in the IDC schedule, does this mean that natural selection has failed to hone all genotypes to the best IDC schedule, or do the differences between genotypes call for different IDC schedules? In terms of IDC traits that can be readily quantified, both the degree of synchrony within each IDC cohort and the times of day at which developmental transitions between IDC stages occur require explanations (Mideo et al., 2013Mideo N. Reece S.E. Smith A.L. Metcalf C.J.E. The Cinderella syndrome: why do malaria-infected cells burst at midnight?.Trends Parasitol. 2013; 29: 10-16Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). When considering correlated traits, it is important to ascertain whether both traits confer benefits and if so, whether they are independently favored by natural selection (Figure 3C). Alternatively, perhaps only one trait is selected and the other occurs as a by-product (Figures 3A and 3B), or neither of the traits are beneficial to parasites (Figure 3D). It is also important to recognize that the selective pressures driving the emergence of a trait may not be the same selective forces responsible for its maintenance. Another consideration is which party is in control of the trait(s) in question; i.e., to what extent do genes belonging to the host and/or parasite control the IDC schedule? Further complexity arises because the balance of host and parasite influences may alter during infections due to the dynamic nature of immune responses, disease symptoms, and parasite densities (Prior et al., 2019Prior K.F. O’Donnell A.J. Rund S.S.C. Savill N.J. van der Veen D.R. Reece S.E. Host circadian rhythms are disrupted during malaria infection in parasite genotype-specific manners.Sci. Rep. 2019; 9: 10905Crossref PubMed Scopus (8) Google Scholar, Rijo-Ferreira et al., 2018Rijo-Ferreira F. Carvalho T. Afonso C. Sanches-Vaz M. Costa R.M. Figueiredo L.M. Takahashi J.S. Sleeping sickness is a circadian disorder.Nat. Commun. 2018; 9: 62Crossref PubMed Scopus (40) Google Scholar). If the IDC is coordinated by a mechanism(s) encoded by parasite genes, then parasites—for better or for worse for their fitness—are actively in control of their IDC schedule. Alternatively, parasites may have an intrinsically arrhythmic IDC and allow host circadian rhythms to impose a schedule that coincidently benefits parasites (Figure 3D). The distinction between host and parasite control is subtle, but disentangling to what extent each party is in control of the IDC schedule, and the costs and benefits they receive, is useful for several reasons. First, it helps narrow down the search for genes and molecular mechanisms that underpin traits expressed during the IDC to the correct party. Second, changes to parasite ecology (e.g., as a consequence of a shift in mosquito biting time) may alter the balance of costs and benefits of a particular IDC schedule. Whether parasites can counter-evolve depends on how much their genes influence the IDC schedule. Third, quantifying how much variation in parasite alleles affects variation in IDC trait values allows predictions to be made for the rate and direction of parasite evolution. The data discussed in the following sections suggest the IDC schedule is a product, at least to some extent, of parasites keeping time, but is also strongly influenced by host circadian rhythms. IDC rhythms can be interrogated using species such as Plasmodium chabaudi, whose asexual stages develop during the IDC in synchrony and transition from one stage to the next at particular times of day (Figures 1A and 1B). Because P. chabaudi is an in vivo model, its IDC can be studied in a more ecologically realistic setting than in vitro models. P. chabaudi’s IDC lasts approximately 24 h and different IDC stages can be distinguished on blood smears by their morphology. However, detecting later IDC stages is challenging because, like the human malaria parasite Plasmodium falciparum, late trophozoites and schizonts sequester in the host tissues via cytoadherence to endothelial cells until schizogony is completed (Mackintosh et al., 2004Mackintosh C.L. Beeson J.G. Marsh K. Clinical features and pathogenesis of severe malaria.Trends Parasitol. 2004; 20: 597-603Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, Miller et al., 2002Miller L.H. Baruch D.I. Marsh K. Doumbo O.K. The pathogenic basis of malaria.Nature. 2002; 415: 673-679Crossref PubMed Scopus (1206) Google Scholar). The following sections illustrate that coupling the ecological complexity of an in vivo model with the reductionism possible with an in vitro model, such as P. falciparum, offers a powerful way to integrate the proximate (“how” or mechanistic) with the ultimate (“why” or evolutionary) explanations for the IDC schedule. While there is clear evidence for timing mechanisms in some parasite taxa, evidence that malaria parasites can organize their IDC schedule is suggestive and indirect. The infectious agent of sleeping sickness, the Trypanosoma brucei parasite, has a circadian clock that controls the timing of expression of over 1,000 genes, mostly associated with its metabolism (Rijo-Ferreira et al., 2017bRijo-Ferreira F. Pinto-Neves D. Barbosa-Morais N.L. Takahashi J.S. Figueiredo L.M. Trypanosoma brucei metabolism is under circadian control.Nat. Microbiol. 2017; 2: 17032Crossref PubMed Scopus (35) Google Scholar). The timing of these rhythms is entrained in vitro by temperature, suggesting that T. brucei actively schedules its daily activities in relation to the active (warm) and rest (cool) phases of the host’s circadian rhythm. Because animals forage and undertake most metabolism in their active phase, aligning its rhythms with temperature may allow T. brucei to coordinate with host feeding events. The fungal pathogen Botrytis cinerea has a circadian clock which regulates how virulent it is to its Arabidopsis thalania hosts, allowing it to overwhelm host defenses that are upregulated at dusk (Hevia et al., 2015Hevia M.A. Canessa P. Müller-Esparza H. Larrondo L.F. A circadian oscillator in the fungus Botrytis cinerea regulates virulence when infecting Arabidopsis thaliana.Proc. Natl. Acad. Sci. USA. 2015; 112: 8744-8749Crossref PubMed Scopus (70) Google Scholar, Larrondo and Canessa, 2018Larrondo L.F. Canessa P. The clock keeps on ticking: emerging roles for circadian regulation in the control of fungal physiology and pathogenesis.in: Fungal Physiology and Immunopathogenesis. Current Topics in Microbiology and Immunology. Volume 422. Springer, 2018Google Scholar). Thanks to work on the model fungus Neurospora crassa, the components and operation of the Botrytis clock are known. However, neither of the parasites Trypanosoma or Plasmodium possesses any genes homologous to the “clock genes” described in Neurospora, cyanobacteria, mammals, or fruit flies. Thus, if malaria parasites have a circadian oscillator, one option would be a classical TTFL operated by novel clock genes. Conventional methods for searching for an oscillator are difficult to apply to P. chabaudi because genome-wide screening approaches require robust and self-sustaining oscillations in vitro, while approaches based on rhythmic gene expression of parasites in vivo are inevitably confounded by synchronous development throughout the IDC of ∼24 h. Using P. falciparum would overcome some of these obstacles because its IDC duration is 48 h and it can be cultivated in vitro (Subudhi et al., 2019Subudhi A.K. O’Donnell A.J. Ramaprasad A. Abkallo H.M. Kaushik A. Ansari H.R. Abdel-Haleem A.M. Rached F.B. Kaneko O. Culleton R. et al.Disruption of the coordination between host circadian rhythms and malaria parasite development alters the duration of the intraerythrocytic cycle.bioRxiv. 2019; https://doi.org/10.1101/791046Crossref Google Scholar). Thus, experiments in which constant (“free-running”) conditions are generated by either not replenishing or continuously replenishing media could use P. falciparum to test for 24 h rhythms in gene expression and protein production, as well as temperature compensation. Such experiments are necessary because observations from P. falciparum and P. chabaudi are not obviously consistent with a circadian clock. For example, the IDC rhythms of P. falciparum break down readily in culture (Schuster, 2002Schuster F.L. Cultivation of plasmodium spp.Clin. Microbiol. Rev. 2002; 15: 355-364Crossref PubMed Scopus (65) Google Scholar), the duration and synchrony of P. chabaudi’s IDC alters when hosts are sick during the peak of infection (K.F.P., S.E.R., Aidan J. O'Donnell, and Nicholas J. Savill, unpublished data), and completion of the IDC across Plasmodium spp. can be slowed by a reduction in temperature (Rojas and Wasserman, 1993Rojas M.O. Wasserman M. Effect of low temperature on the in vitro growth of Plasmodium falciparum.J. Eukaryot. Microbiol. 1993; 40: 149-152Crossref PubMed Scopus (13) Google Scholar). However, using observations based on IDC development to reject the presence of a circadian clock is premature. If these conditions de-couple the ability of a clock’s readout to schedule the IDC, then a disrupted IDC does not indicate the absence of a clock. For instance, perhaps a clock keeps on ticking with a 24 h duration, despite the IDC being slowed by cooling. Instead of a sophisticated circadian oscillator such as a TTFL, parasites may keep time using a rudimentary clock. For example, an “hourglass timer” (whereby the hourglass is “turned” when a signal is received) would allow parasites to set the IDC schedule on detection of a time-of-day signal in the environment, but would not generate self-sustaining oscillations (Pittayakanchit et al., 2018Pittayakanchit W. Lu Z. Chew J. Rust M.J. Murugan A. Biophysical clocks face a trade-off between internal and external noise resistance.eLife. 2018; 7: e37624Crossref PubMed Scopus (18) Google Scholar). An even simpler strategy would be to make IDC transitions in response to the appearance or disappearance of a cue(s) coupled to specific times of day. In evolutionary ecology, such responses to environmental factors are called “adaptive phenotypic plasticity” (Pigliucci et al., 2006Pigliucci M. Murren C.J. Schlichting C.D. Phenotypic plasticity and evolution by genetic assimilation.J. Exp. Biol. 2006; 209: 2362-2367Crossref PubMed Scopus (608) Google Scholar). A phenotypically plastic strategy contrasts from an hourglass timer, in that plasticity sets the duration of IDC stages by stop/go environmental triggers, whereas an hourglass sets the timing of a transition from one IDC stage to the next until the IDC is completed. In many cases of adaptive phenotypic plasticity, organisms do not respond directly to the environmental factor that matters for fitness, but to a proxy that correlates with it. Proxies are particularly useful when the important environmental factor is hard to measure accurately or if the organism needs to prepare in advan" @default.
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• W3005983517 date "2020-02-01" @default.
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• W3005983517 title "Periodic Parasites and Daily Host Rhythms" @default.
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