The Cinderella syndrome: why do malaria-infected cells burst at midnight?

An interesting quirk of many malaria infections is that all parasites within a host – millions of them – progress through their cell cycle synchronously. This surprising coordination has long been recognized, yet there is little understanding of what controls it or why it has evolved. Interestingly, the conventional explanation for coordinated development in other parasite species does not seem to apply here. We argue that for malaria parasites, a critical question has yet to be answered: is the coordination due to parasites bursting at the same time or at a particular time? We explicitly delineate these fundamentally different scenarios, possible underlying mechanistic explanations and evolutionary drivers, and discuss the existing corroborating data and key evidence needed to solve this evolutionary mystery. An interesting quirk of many malaria infections is that all parasites within a host – millions of them – progress through their cell cycle synchronously. This surprising coordination has long been recognized, yet there is little understanding of what controls it or why it has evolved. Interestingly, the conventional explanation for coordinated development in other parasite species does not seem to apply here. We argue that for malaria parasites, a critical question has yet to be answered: is the coordination due to parasites bursting at the same time or at a particular time? We explicitly delineate these fundamentally different scenarios, possible underlying mechanistic explanations and evolutionary drivers, and discuss the existing corroborating data and key evidence needed to solve this evolutionary mystery. “…sa marraine lui recommanda sur toutes choses de ne pas passer minuit, l’avertissant que si elle demeurait au bal un moment davantage, son carrosse redeviendrait citrouille…”“Her godmother bade her not to stay beyond midnight whatever happened, warning her that if she remained at the ball a moment longer, her coach would again become a pumpkin” – Charles Perrault For most malaria parasite species, the parasite cell cycle within a host is precisely coordinated – malaria parasites invade host red blood cells (RBCs), replicate asexually, and then release the next cohort of parasites in a burst that is synchronized across all parasites within the infection. Intriguingly, this synchronized bursting appears to occur at a particular time: Plasmodium chabaudi (rodent malaria) parasites, for instance, tend to synchronize bursting around midnight 1Landau I. Gautret P. Animal models: rodents.in: Sherman I.W. Malaria: Parasite Biology, Pathogenesis, and Protection. American Society for Microbiology, 1998: 401-417Google Scholar (thus inspiring our title, although it is important to point out that other Plasmodium species burst at different times of the day/night). Although cell cycle duration varies across malaria parasite species, it is generally a multiple of 24 h (Figure 1). Indeed, the periodicity of fever that follows the simultaneous bursting of RBCs at the end of the cell cycle was once used as a diagnostic tool (e.g., the human parasites Plasmodium falciparum and Plasmodium malariae have 48 and 72 h cycles, respectively, leading to ‘tertian’ or ‘quartan’ fevers 2Garcia C.R.S. et al.Tertian and quartan fevers: temporal regulation in malarial infection.J. Biol. Rhythms. 2001; 16: 436-443Crossref PubMed Scopus (52) Google Scholar). Despite an early interest in evolutionary explanations for the coordination of malaria parasites (e.g., 3Hawking F. et al.The biological purpose of the blood cycles of the malaria parasite Plasmodium cynomolgi.Lancet. 1966; ii: 422-424Abstract Google Scholar), work in recent years has focused on identifying proximate mechanisms for such rhythms. The 24-h cell cycles (or multiples thereof) are suggestive of a circadian basis, and the search continues for homologs of clock genes in the parasite genome 4Sherman I.W. Shocks and clocks.Adv. Parasitol. 2008; 67: 271-277Crossref Scopus (1) Google Scholar and host circadian cues that could influence parasite cell cycles (e.g., melatonin 5Hotta C.T. et al.Calcium-dependent modulation by melatonin of the circadian rhythm in malarial parasites.Nat. Cell Biol. 2000; 2: 466-468Crossref PubMed Scopus (163) Google Scholar). By uncovering these mechanisms it may be possible to manipulate parasite schedules as a form of control. Interestingly, changes to parasite rhythms have been implicated in resistance to current front-line antimalarial drugs (artemisinin derivatives); parasites are thought to enter a quiescent state, delaying their development until the activity of drugs in their host has diminished (e.g., 6Witkowski B. et al.Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism.Antimicrob. 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The evolutionary of the coordination of malaria parasite cell cycles a for this and other evolutionary in the of the mechanisms in rhythms in malaria and the of malaria to parasite forms that are by a of The that the production of is coordinated that and 3Hawking F. et al.The biological purpose of the blood cycles of the malaria parasite Plasmodium cynomolgi.Lancet. 1966; ii: 422-424Abstract Google Scholar, of of the J. Parasitol. PubMed Scopus (22) Google Scholar, F. et and cycles of malaria parasites in blood – their purpose production and PubMed Scopus Google of underlying have been the that synchronized of synchronized bursting of all as long as P. falciparum and of Plasmodium falciparum and Plasmodium in to malaria and Rev. 2011; PubMed Scopus Google Scholar), in could to in of many by the time is the that in the for a day (or only of Although that the of a malaria species have times on the of P. of Plasmodium to the 1999; 6: Google Scholar, et in the rodent malaria Plasmodium 2003; PubMed Scopus Google for P. falciparum in and of Plasmodium falciparum and Plasmodium in to malaria and Rev. 2011; PubMed Scopus Google Scholar, et the of Plasmodium J. PubMed Scopus Google Scholar]). it that with is a that most have to (e.g., et of a circadian rhythm in the of the of Plasmodium falciparum to J. Parasitol. 6: PubMed Scopus (22) Google Scholar, et on the periodicity of Plasmodium falciparum in human 2000; PubMed Scopus Google Scholar, Plasmodium falciparum their and PubMed Scopus Google Scholar]). has been that data on are to the P. Plasmodium falciparum 2001; PubMed Scopus Google Scholar]. We that data are to understand rhythms in and argue that the of evidence against the is of malaria to parasite forms that are by a of The that the production of is coordinated that and 3Hawking F. et al.The biological purpose of the blood cycles of the malaria parasite Plasmodium cynomolgi.Lancet. 1966; ii: 422-424Abstract Google Scholar, of of the J. Parasitol. PubMed Scopus (22) Google Scholar, F. et and cycles of malaria parasites in blood – their purpose production and PubMed Scopus Google of underlying have been the that synchronized of synchronized bursting of all as long as P. falciparum and of Plasmodium falciparum and Plasmodium in to malaria and Rev. 2011; PubMed Scopus Google Scholar), in could to in of many by the time is the that in the for a day (or only of Although that the of a malaria species have times on the of P. of Plasmodium to the 1999; 6: Google Scholar, et in the rodent malaria Plasmodium 2003; PubMed Scopus Google for P. falciparum in and of Plasmodium falciparum and Plasmodium in to malaria and Rev. 2011; PubMed Scopus Google Scholar, et the of Plasmodium J. PubMed Scopus Google Scholar]). it that with is a that most have to (e.g., et of a circadian rhythm in the of the of Plasmodium falciparum to J. Parasitol. 6: PubMed Scopus (22) Google Scholar, et on the periodicity of Plasmodium falciparum in human 2000; PubMed Scopus Google Scholar, Plasmodium falciparum their and PubMed Scopus Google Scholar]). has been that data on are to the P. Plasmodium falciparum 2001; PubMed Scopus Google Scholar]. We that data are to understand rhythms in and argue that the of evidence against the is our what has been from of malaria parasite cell cycles is an that the coordination could be the of for synchrony or timing in most evolutionary have that parasites an evolutionary from of these and the For to synchrony and timing as that in these are the of underlying coordination may evolutionary to parasites, may and may be under the of the evolution of coordination in this possible and in of cell cycles is an of malaria parasites that their For example, synchrony could parasites with in from this parasites could (e.g., a development of the of and to development by from in of Plasmodium J. 2003; Google Scholar]), could have their or could timing cues from host circadian rhythms 2Garcia C.R.S. et al.Tertian and quartan fevers: temporal regulation in malarial infection.J. Biol. Rhythms. 2001; 16: 436-443Crossref PubMed Scopus (52) Google Scholar, C.T. et al.Calcium-dependent modulation by melatonin of the circadian rhythm in malarial parasites.Nat. Cell Biol. 2000; 2: 466-468Crossref PubMed Scopus (163) Google Scholar. the synchrony and timing would not be and synchronized parasites in different hosts may burst at different times of the parasites are time cues to bursting at a time would be a of for synchrony does not an to timing of bursting is an of malaria parasites RBCs bursting at a particular time of the For example, timing could parasites to a circadian release of parasite or the appearance of a particular schedule the same to all parasites in an synchrony would be a of the evolution of timing all parasites would be on the same could set the timing of cell cycle development by cues from the host circadian rhythm or their and timing of cell cycles are of malaria parasites and may be for through different other trait a that some of and synchrony timing of cell cycles is an of malaria the coordination of cell cycles some to For example, particular parasite cell cycle to a particular time of day could the of with circadian rhythms of malaria constraints on and Biol. 2008; PubMed Scopus Google Scholar] or could by parasites for host synchrony timing of cell cycles is an of malaria parasites or parasites are their cycle and the cell cycle is by physiological or of or hosts and parasites in this the coordination of parasite development may be or to hosts or malaria cell cycle and parasites replicate within host RBCs bursting and the parasites with the to invade other RBCs and a new cycle of the evolutionary significance of the periodicity of malaria infections the of (Figure the constraints on malaria parasite cell and physiological constraints on cell The processes of and parasite that release a Although malaria parasites all to and the cell 12: PubMed Scopus Google Scholar] the the of could the time until a is to Plasmodium species that different of may have different of the other end of the once the have been there may be an on bursting as parasites may be by processes that through of the or bursting under et and the of Plasmodium red blood 2003; PubMed Scopus Google Scholar]. 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