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Calcium-dependent modulation by melatonin of the circadian rhythm in malarial parasites.

Nature Cell Biology volume 2, pages 466–468 (2000)Cite this article

The development of malarial parasites is a complex process involving both intracellular and extracellular phases. Intra-erythrocytic maturation proceeds through well-defined stages, termed rings, trophozoites and schizonts. In vivo, transition to a new stage and invasion of new erythrocytes are highly synchronous1. The timing of these processes varies between Plasmodium species, but is always a multiple of 24 h. The simultaneous appearance of billions of individual parasites in the bloodstream may represent an efficient evolutionary strategy to escape the defence mechanisms of the host. The synchronicity of these processes is rapidly lost in culture, indicating the possible involvement of a host-derived signal, although the nature of this signal is presently unknown. Here we show that the hormone melatonin modifies the development of malarial parasites in vitro, that in vivo surgical ablation of the pineal gland leads to reduced synchronicity in the maturation process of Plasmodium, an effect that is reversed upon treatment with melatonin, and that in vivo inhibition of melatonin receptors mimics the effect of pinealectomy. We also demonstrate that melatonin, through activation of specific receptors coupled to phospholipase C activation, causes release of Ca2+ from the intracellular stores of Plasmodium grown in vitro. We therefore propose that circadian changes in melatonin concentration in the host represent a key signal that controls synchronous maturation of Plasmodium in vivo.

Figure 1a, b shows that prolonged in vitro incubation of Plasmodium with melatonin results in acceleration of the developmental process towards more mature forms (schizonts). It is therefore to be expected that if this melatonin effect is preserved in vivo, where host melatonin secretion occurs once a day at a very precise time (around midnight), the net result will be synchronization of the parasite cell cycle. It follows that inhibition of melatonin production would result in desynchronization of Plasmodium maturation, giving rise to a much broader variety of parasite forms in infected red blood cells. This is indeed what is found in vivo after surgical ablation of the pineal gland4. The relative proportions of the different parasite forms in sham-operated animals were heavily biased towards the trophozoite stage (blood was withdrawn at 6 pm (1800 h)), whereas in pinealectomized animals 72 h after injection of an originally synchronous parasite population, the relative percentages of the different forms were quite different — the number of rings was doubled and the number of trophozoites was correspondingly reduced ( Fig. 1c). When pinealectomized animals were injected with melatonin, using a protocol that mimics endogenous melatonin production (2 injections per day at 2200 h and 2400 h), the relative percentages of the different forms were indistinguishable from those of controls.

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Figure 1: Melatonin increases parasitemia and promotes maturation of P. falciparum and P. chabaudi.
Figure 2: Effect of melatonin on cytosolic [Ca2+]i in intact P. chabaudi cells.

References

  1. Doerig, C. D. Parasitol. Today 13, 297–313 (1997).

    Article  Google Scholar 

  2. Klein, D. C., Auerbach, D. A., Namboodiri, M. A. A. & Wheler, G. H. T. in The Pineal Gland, Anatomy and Biochemistry (ed. Reiter, R.) 199–227 (CRC, Boca Raton, 1981).

  3. Cassone, V. M. & Natesan, A. K. J. Biol. Rhythms 12, 489–497 (1997).

    Article  CAS  Google Scholar 

  4. Lopes, C., DeLyra, J. L., Markus, R. P. & Mariano, M. J. Pineal Res. 23, 72–78, (1997).

    Article  CAS  Google Scholar 

  5. Vivien-Roels, B. et al. J. Biol. Rhythms 13, 403– 409 (1998)

    Article  CAS  Google Scholar 

  6. Arnold, J. D., Martin, D. C., & Lalli, F. J. Parasitol. 55, 597– 608 (1969).

    Article  CAS  Google Scholar 

  7. Hawking, F., Gammage, K. & Worms, M. J. Parasitology 65, 189– 201 (1972).

    Article  CAS  Google Scholar 

  8. Cambie, G., Landau, I. & Chabaud, A. G. Comptes Rendus Acad. Sci. Paris 310, 183–188 (1990).

    CAS  Google Scholar 

  9. David, P. H., Hommel, M., Bennichou, J. C., Eisen, H. A. M. & Pereira da Silva, L. H. Proc. Natl Acad. Sci USA 75, 5081–5084 ( 1978).

    Article  CAS  Google Scholar 

  10. Arnold, J. D., Berger, A. & Martin, D. C. J. Parasitol. 55, 609– 616 (1969).

    Article  CAS  Google Scholar 

  11. Eison, A. S. & Mullins, U. L. Life Sci. 53, 393–398 (1993).

    Article  Google Scholar 

  12. Popova, J. S & Dubocovich, M. L. J. Neurochem. 64, 130–138 (1995).

    Article  CAS  Google Scholar 

  13. Tsim, S. T., Wong, J. T. Y. & Wong, Y. H. J. Cell Sci 110, 1387– 1393 (1997).

    CAS  PubMed  Google Scholar 

  14. Pozzan, T., Rizzuto, R., Volpe, P. & Meldolesi, J. Physiol. Rev. 74, 595–636 ( 1994).

    Article  CAS  Google Scholar 

  15. Passos, A. P. D. & Garcia, C. R. S. Biophys. Res. Commun. 245, 155–160 (1998).

    Article  CAS  Google Scholar 

  16. Garcia, C. R. S. et al. Eur. J. Cell Biol. 71, 409– 413 (1996).

    CAS  PubMed  Google Scholar 

  17. Garcia, C. R. S. et al. Eur. J. Cell Biol. 76, 133– 138 (1998).

    Article  CAS  Google Scholar 

  18. Garcia, C. R. S. Parasitol. Today 15, 488–491 (1999).

    Article  CAS  Google Scholar 

  19. Bell, A., Wernlis, B. & Franklin, R. M. Biochem. Pharmacol 48, 495 –503 (1994).

    Article  CAS  Google Scholar 

  20. Trager, W. & Jensen, J. B. Science 193, 673–675 (1976).

    Article  CAS  Google Scholar 

  21. Di Virgilio, F., Steinberg, T. H., Swanson, J. A. & Silverstein, S. C. J. Immunol. 140, 915–920 (1987).

    Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Fundação de Amparo à Pesquisa de São Paulo (FAPESP) and from the Conselho Nacional de Desenvolvimento Científico e Tecnólogico (CNPq) to C.R.S.G. and R.P.M., and by grants from the University of Padova, from UNESCO and from the Harvard Armenise Foundation to T.P. We thank S. D. Santi from SUCEN for help with P. falciparum culture and A. Thomas for helpful discussions .

Correspondence and requests for materials should be addressed to C.R.S.G.

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  1. Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, 05508-90, Brasil

    Carlos T. Hotta, Marcos L. Gazarini, Flávio H. Beraldo, Fernando P. Varotti, Cristiane Lopes, Regina P. Markus & Célia R. S. Garcia

  2. Dipartimento di Scienze Biomediche Sperimentali, Centro CNR ‘Biomembrane’, Universita’ di Padova, Padova, 35121, Italy

    Tullio Pozzan

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Correspondence to Célia R. S. Garcia.

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Hotta, C., Gazarini, M., Beraldo, F. et al. Calcium-dependent modulation by melatonin of the circadian rhythm in malarial parasites.. Nat Cell Biol 2, 466–468 (2000). https://doi.org/10.1038/35017112

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