Skip to main content
Proceedings of the Royal Society B: Biological Sciences logoLink to Proceedings of the Royal Society B: Biological Sciences
. 1997 Apr 22;264(1381):553–559. doi: 10.1098/rspb.1997.0079

Adaptive changes in Plasmodium transmission strategies following chloroquine chemotherapy.

A G Buckling 1, L H Taylor 1, J M Carlton 1, A F Read 1
PMCID: PMC1688398  PMID: 9149425

Abstract

Both theory and data suggest that malaria parasites divert resources from within-host replication to the production of transmission stages (gametocytes) when conditions deteriorate. Increased investment into transmission stages should therefore follow subcurative treatment with antimalarial drugs, but relevant clinical studies necessarily lack adequate control groups. We therefore carried out controlled experiments to test this hypothesis, using a rodent malaria (Plasmodium chabaudi) model. Infections treated with a subcurative dose of the antimalarial chloroquine showed an earlier peak and a greater rate of gametocyte production relative to untreated controls. These alterations led to correlated changes in infectivity to mosquitoes, with the consequence that chloroquine treatment had no effect on the proportion of mosquitoes infected. Treatment of human malaria commonly does not result in complete parasite clearance. If surviving parasites produce compensatory increases in their rate of gametocyte production similar to those reported here, such treatment may have minimal effect on decreasing, and may actually increase, transmission. Importantly, if increased investment in transmission is a generalized stress response, the effect might be observed following a variety of antimalarial treatments, including other drugs and potential vaccines. Similar parasite life history counter-adaptations to intervention strategies are likely to occur in many disease-causing organisms.

Full Text

The Full Text of this article is available as a PDF (315.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alano P., Carter R. Sexual differentiation in malaria parasites. Annu Rev Microbiol. 1990;44:429–449. doi: 10.1146/annurev.mi.44.100190.002241. [DOI] [PubMed] [Google Scholar]
  2. Brockelman C. R. Conditions favoring gametocytogenesis in the continuous culture of Plasmodium falciparum. J Protozool. 1982 Aug;29(3):454–458. doi: 10.1111/j.1550-7408.1982.tb05432.x. [DOI] [PubMed] [Google Scholar]
  3. Bruce M. C., Alano P., Duthie S., Carter R. Commitment of the malaria parasite Plasmodium falciparum to sexual and asexual development. Parasitology. 1990 Apr;100(Pt 2):191–200. doi: 10.1017/s0031182000061199. [DOI] [PubMed] [Google Scholar]
  4. Burkot T. R., Williams J. L., Schneider I. Infectivity to mosquitoes of Plasmodium falciparum clones grown in vitro from the same isolate. Trans R Soc Trop Med Hyg. 1984;78(3):339–341. doi: 10.1016/0035-9203(84)90114-7. [DOI] [PubMed] [Google Scholar]
  5. Cambie G., Verdier F., Gaudebout C., Clavier F., Ginsburg H. The pharmacokinetics of chloroquine in healthy and Plasmodium chabaudi-infected mice: implications for chronotherapy. Parasite. 1994 Sep;1(3):219–226. doi: 10.1051/parasite/1994013219. [DOI] [PubMed] [Google Scholar]
  6. Carter R., Miller L. H. Evidence for environmental modulation of gametocytogenesis in Plasmodium falciparum in continuous culture. Bull World Health Organ. 1979;57 (Suppl 1):37–52. [PMC free article] [PubMed] [Google Scholar]
  7. Crowl T. A., Covich A. P. Predator-induced life-history shifts in a freshwater snail. Science. 1990 Feb 23;247(4945):949–951. doi: 10.1126/science.247.4945.949. [DOI] [PubMed] [Google Scholar]
  8. Graves P. M., Burkot T. R., Carter R., Cattani J. A., Lagog M., Parker J., Brabin B. J., Gibson F. D., Bradley D. J., Alpers M. P. Measurement of malarial infectivity of human populations to mosquitoes in the Madang area, Papua, New Guinea. Parasitology. 1988 Apr;96(Pt 2):251–263. doi: 10.1017/s003118200005825x. [DOI] [PubMed] [Google Scholar]
  9. Graves P. M., Carter R., McNeill K. M. Gametocyte production in cloned lines of Plasmodium falciparum. Am J Trop Med Hyg. 1984 Nov;33(6):1045–1050. doi: 10.4269/ajtmh.1984.33.1045. [DOI] [PubMed] [Google Scholar]
  10. Handunnetti S. M., Gunewardena D. M., Pathirana P. P., Ekanayake K., Weerasinghe S., Mendis K. N. Features of recrudescent chloroquine-resistant Plasmodium falciparum infections confer a survival advantage on parasites and have implications for disease control. Trans R Soc Trop Med Hyg. 1996 Sep-Oct;90(5):563–567. doi: 10.1016/s0035-9203(96)90325-9. [DOI] [PubMed] [Google Scholar]
  11. Hogh B., Thompson R., Hetzel C., Fleck S. L., Kruse N. A., Jones I., Dgedge M., Barreto J., Sinden R. E. Specific and nonspecific responses to Plasmodium falciparum blood-stage parasites and observations on the gametocytemia in schoolchildren living in a malaria-endemic area of Mozambique. Am J Trop Med Hyg. 1995 Jan;52(1):50–59. doi: 10.4269/ajtmh.1995.52.50. [DOI] [PubMed] [Google Scholar]
  12. Ichimori K., Curtis C. F., Targett G. A. The effects of chloroquine on the infectivity of chloroquine-sensitive and -resistant populations of Plasmodium yoelii nigeriensis to mosquitoes. Parasitology. 1990 Jun;100(Pt 3):377–381. doi: 10.1017/s0031182000078641. [DOI] [PubMed] [Google Scholar]
  13. JEFFERY G. M., YOUNG M. D., EYLES D. E. The treatment of Plasmodium falciparum infection with chloroquine, with a note on infectivity to mosquitoes of primaquine- and pyrimethamine-treated cases. Am J Hyg. 1956 Jul;64(1):1–11. doi: 10.1093/oxfordjournals.aje.a119818. [DOI] [PubMed] [Google Scholar]
  14. Jarra W., Brown K. N. Protective immunity to malaria: studies with cloned lines of rodent malaria in CBA/Ca mice. IV. The specificity of mechanisms resulting in crisis and resolution of the primary acute phase parasitaemia of Plasmodium chabaudi chabaudi and P. yoelii yoelii. Parasite Immunol. 1989 Jan;11(1):1–13. doi: 10.1111/j.1365-3024.1989.tb00644.x. [DOI] [PubMed] [Google Scholar]
  15. Jensen J. B. Observations on gametogenesis in Plasmodium falciparum from continuous culture. J Protozool. 1979 Feb;26(1):129–132. doi: 10.1111/j.1550-7408.1979.tb02748.x. [DOI] [PubMed] [Google Scholar]
  16. Lines J. D., Wilkes T. J., Lyimo E. O. Human malaria infectiousness measured by age-specific sporozoite rates in Anopheles gambiae in Tanzania. Parasitology. 1991 Apr;102(Pt 2):167–177. doi: 10.1017/s0031182000062454. [DOI] [PubMed] [Google Scholar]
  17. McCarthy V. C., Clyde D. F. Influence of sulfalene upon gametocytogenesis of Plasmodium falciparum and subsequent infection patterns in Anopheles stephensi. Exp Parasitol. 1973 Feb;33(1):73–78. doi: 10.1016/0014-4894(73)90010-6. [DOI] [PubMed] [Google Scholar]
  18. RAMAKRISHNAN S. P., YOUNG M. D., JEFFERY G. M., BURGESS R. W., McLENDON S. B. The effect of single and multiple doses of paludrine upon Plasmodium falciparum. Am J Hyg. 1952 Mar;55(2):239–245. doi: 10.1093/oxfordjournals.aje.a119517. [DOI] [PubMed] [Google Scholar]
  19. Ramkaran A. E., Peters W. Infectivity of chloroquine resistant Plasmodium berghei to Anopheles stephensi enhanced by chloroquine. Nature. 1969 Aug 9;223(5206):635–636. doi: 10.1038/223635a0. [DOI] [PubMed] [Google Scholar]
  20. Rice W. R., Gaines S. D. Extending nondirectional heterogeneity tests to evaluate simply ordered alternative hypotheses. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):225–226. doi: 10.1073/pnas.91.1.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. SHUTE P. G., MARYON M. A study of gametocytes in a West African strain of Plasmodium falciparum. Trans R Soc Trop Med Hyg. 1951 Feb;44(4):421–438. doi: 10.1016/s0035-9203(51)80020-8. [DOI] [PubMed] [Google Scholar]
  22. Shine R. Propagule size and parental care: the "safe harbor" hypothesis. J Theor Biol. 1978 Dec 21;75(4):417–424. doi: 10.1016/0022-5193(78)90353-3. [DOI] [PubMed] [Google Scholar]
  23. Sinden R. E., Butcher G. A., Billker O., Fleck S. L. Regulation of infectivity of Plasmodium to the mosquito vector. Adv Parasitol. 1996;38:53–117. doi: 10.1016/s0065-308x(08)60033-0. [DOI] [PubMed] [Google Scholar]
  24. Sinden R. E. Sexual development of malarial parasites. Adv Parasitol. 1983;22:153–216. doi: 10.1016/s0065-308x(08)60462-5. [DOI] [PubMed] [Google Scholar]
  25. Smalley M. E. Plasmodium falciparum gametocytogenesis in vitro. Nature. 1976 Nov 18;264(5583):271–272. doi: 10.1038/264271a0. [DOI] [PubMed] [Google Scholar]
  26. Strickland G. T., Khaliq A. A., Sarwar M., Hassan H., Pervez M., Fox E. Effects of Fansidar on chloroquine-resistant Plasmodium falciparum in Pakistan. Am J Trop Med Hyg. 1986 Jan;35(1):61–65. doi: 10.4269/ajtmh.1986.35.61. [DOI] [PubMed] [Google Scholar]
  27. Tin F., Nyunt-Hlaing Comparative drug trial of a sulfadoxine/pyrimethamine and a sulfalene/pyrimethamine combination against Plasmodium falciparum infections in semi-immune populations of Burma. Southeast Asian J Trop Med Public Health. 1984 Jun;15(2):238–248. [PubMed] [Google Scholar]
  28. Wernsdorfer W. H. Epidemiology of drug resistance in malaria. Acta Trop. 1994 Mar;56(2-3):143–156. doi: 10.1016/0001-706x(94)90060-4. [DOI] [PubMed] [Google Scholar]
  29. Wilkinson R. N., Noeypatimanondh S., Gould D. J. Infectivity of falciparum malaria patients for anopheline mosquitoes before and after chloroquine treatment. Trans R Soc Trop Med Hyg. 1976;70(4):306–307. doi: 10.1016/0035-9203(76)90083-3. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES