Parasitology Research

, Volume 108, Issue 1, pp 247–252 | Cite as

The hypnozoite concept, with particular reference to malaria

  • Miles B. MarkusEmail author
Short Communcation


In 1978, the nature of the hypnozoite was discussed in an article that appeared in a relatively obscure journal, which is also where the term was adopted for Plasmodium (a little-known fact). As a result, that commentary on the use of the word “hypnozoite” has been almost completely overlooked. Although the publication is now more than three decades old, the analysis remains valid today. It is explained in the present paper that like “merozoite” and “sporozoite”, the name “hypnozoite” is applicable not only to a latent stage in the life cycle of Plasmodium but to some apparently dormant forms of other kinds of apicomplexan parasites as well. Merozoites of different genera of parasitic protozoa are not necessarily the same biologically and/or otherwise. Similarly, although the hypnozoite concept relates primarily to pre-merozoite stages, some atypical post-divisional apicomplexan forms might also be hypnozoites. Examples are likewise given of latent organisms that, in contrast, are clearly not hypnozoites, such as dormant merozoites in malaria infections. Lastly, the plasmodial hypnozoite is placed in context in relation to the relatively unfamiliar (nomenclaturally) malarial bradysporozoite, chronozoite, dormozoite, merophore, merosome and x body. This paper is based on a presentation by the author, as a Life Member of the American Society of Tropical Medicine and Hygiene, to its 59th Annual Meeting in Atlanta, Georgia, USA, 3–7 November 2010.


Malaria Plasmodium Felis Apicomplexan Parasite Plasmodium Malariae 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Amino R, Thiberge S, Martin B, Celli S, Shorte S, Frischknecht F, Ménard R (2006) Quantitative imaging of Plasmodium transmission from mosquito to mammal. Nat Med 12:220–224CrossRefPubMedGoogle Scholar
  2. Baer K, Klotz C, Kappe SHI, Schnieder T, Frevert U (2007) Release of hepatic Plasmodium yoelii merozoites into the pulmonary microvasculature. PLoS Pathog 3(11):e171CrossRefPubMedGoogle Scholar
  3. Ball SJ, Pittilo RM, Long PL (1989) Intestinal and extraintestinal life cycles of eimeriid coccidia. Adv Parasitol 28:1–54CrossRefPubMedGoogle Scholar
  4. Barta JR, Schrenzel MD, Carreno R, Rideout BA (2005) The genus Atoxoplasma (Garnham 1950) as a junior objective synonym of the genus Isospora (Schneider 1881) species infecting birds and resurrection of Cystoisospora (Frenkel 1977) as the correct genus for Isospora species infecting mammals. J Parasitol 91:726–727CrossRefPubMedGoogle Scholar
  5. Beyer TV, Sidorenko NV (1984) Karyolysus sp. (Haemogregarinidae, Adeleida, Apicomplexa): host-parasite relationships of persisting stages. J Protozool 31:513–517Google Scholar
  6. Bledsoe B (1980) Transmission studies with Sarcocystis idahoensis of deer mice (Peromyscus maniculatus) and gopher snakes (Pituophis melanoleucus). J Wildl Dis 16:195–200PubMedGoogle Scholar
  7. Bray RS, Krotoski WA, Cogswell FB, Garnham PCC, Rodriguez M, Guy MW, Gwadz RW, Sinden RE, Targett GAT, Draper CC, Killick-Kendrick R (1985) Observations on early and late post-sporozoite tissue stages in primate malaria. III. Further attempts to find early forms and to correlate hypnozoites with growing exo-erythrocytic schizonts and parasitaemic relapses in Plasmodium cynomolgi bastianellii infections. Trans R Soc Trop Med Hyg 79:269–273CrossRefPubMedGoogle Scholar
  8. Bristovetzky M, Paperna I (1990) Life cycle and transmission of Schellackia cf. agamae, a parasite of the starred lizard Agama stellio. Int J Parasitol 20:883–892CrossRefGoogle Scholar
  9. Bruce-Chwatt LJ (1984) Terminology of relapsing malaria: enigma variations. Trans R Soc Trop Med Hyg 78:844–845CrossRefPubMedGoogle Scholar
  10. Chen N, Auliff A, Rieckmann K, Gatton M, Cheng Q (2007) Relapses of Plasmodium vivax infection result from clonal hypnozoites activated at predetermined intervals. J Infect Dis 195:934–941CrossRefPubMedGoogle Scholar
  11. Cogswell FB, Collins WE, Krotoski WA, Lowrie RC (1991) Hypnozoites of Plasmodium simiovale. Am J Trop Med Hyg 45:211–213PubMedGoogle Scholar
  12. Collins WE (2007) Further understanding the nature of relapse of Plasmodium vivax infection. J Infect Dis 195:919–920CrossRefPubMedGoogle Scholar
  13. Collins WE, Jeffery GM (2007) Plasmodium malariae: parasite and disease. Clin Microbiol Rev 20:579–592CrossRefPubMedGoogle Scholar
  14. Corradetti A (1985) About the hypnozoites of the vivax-like group of plasmodia. Trans R Soc Trop Med Hyg 79:879–880CrossRefPubMedGoogle Scholar
  15. Focà E, Zulli R, Buelli F, De Vecchi M, Regazzoli A, Castelli F (2009) P. falciparum malaria recrudescence in a cancer patient. Le Infezioni Med 1:33–34Google Scholar
  16. Galinski MR, Barnwell JW (2008) Plasmodium vivax: who cares? Malaria J 7(suppl 1):59Google Scholar
  17. Greenwood T, Vikerfors T, Sjöberg M, Skeppner G, Färnert A (2008) Febrile Plasmodium falciparum malaria 4 years after exposure in a man with sickle cell disease. Clin Infect Dis 47:e39–e41CrossRefPubMedGoogle Scholar
  18. Heydorn AO, Rommel M (1972a) Beiträge zum Lebenszyklus der Sarkosporidien. II. Hund und Katze als Überträger der Sarkosporidien des Rindes. Berl Münch Tierärztl Wochenschr 85:121–123PubMedGoogle Scholar
  19. Heydorn AO, Rommel M (1972b) Beiträge zum Lebenszyklus der Sarkosporidien. IV. Entwicklungsstadien von S. fusiformis in der Dunndarmschleimhaut der Katze. Berl Münch Tierärztl Wochenschr 85:333–336PubMedGoogle Scholar
  20. Hollingdale MR (1992) Is culture of the entire Plasmodium cycle, in vitro, now a reality? Parasitol Today 8:223CrossRefPubMedGoogle Scholar
  21. Hollingdale MR, Collins WE, Campbell CC (1986) In vitro culture of exoerythrocytic parasites of the North Korean strain of Plasmodium vivax in hepatoma cells. Am J Trop Med Hyg 35:275–276PubMedGoogle Scholar
  22. House BL, Hollingdale MR, Sacci JB, Richie TL (2009) Functional immunoassays using an in-vitro malaria liver-stage infection model: where do we go from here? Trends Parasitol 25:525–533CrossRefPubMedGoogle Scholar
  23. Imwong M, Snounou G, Pukrittayakamee S, Tanomsing N, Kim JR, Nandy A, Guthmann J, Nosten F, Carlton J, Looareesuwan S, Nair S, Sudimack D, Day NPJ, Anderson TJC, White NJ (2007) Relapses of Plasmodium vivax infection usually result from activation of heterologous hypnozoites. J Infect Dis 195:927–933CrossRefPubMedGoogle Scholar
  24. Jiang JB, Bray RS, Krotoski WA, Canning EU, Liang DS, Huang JC, Liao JY, Li DS, Lun ZR, Landau I (1988) Observations on early and late post-sporozoite tissue stages in primate malaria. V. The effect of pyrimethamine and proguanil upon tissue hypnozoites and schizonts of Plasmodium cynomolgi bastianellii. Trans R Soc Trop Med Hyg 82:56–58CrossRefPubMedGoogle Scholar
  25. Koudela B, Modrý D (1999) Extraintestinal stages of coccidia in liver of Schneider's skink Eumeces schneideri (Sauria: Scincidae) from northern Egypt. Folia Parasitol 46:99–102Google Scholar
  26. Krotoski WA (1985) About the hypnozoites of the vivax-like group of plasmodia: a reply. Trans R Soc Trop Med Hyg 79:880–881CrossRefGoogle Scholar
  27. Krotoski WA, Collins WE (1982) Failure to detect hypnozoites in hepatic tissue containing exoerythrocytic schizonts of Plasmodium knowlesi. Am J Trop Med Hyg 31:854–856PubMedGoogle Scholar
  28. Krotoski WA, Krotoski DM, Garnham PCC, Bray RS, Killick-Kendrick R, Draper CC, Targett GAT, Guy MW (1980) Relapses in primate malaria: discovery of two populations of exoerythrocytic stages. Preliminary note. Brit Med J 1:153–154CrossRefGoogle Scholar
  29. Krotoski WA, Garnham PCC, Bray RS, Krotoski DM, Killick-Kendrick R, Draper CC, Targett GAT, Guy MW (1982a) Observations on early and late post-sporozoite tissue stages in primate malaria. I. Discovery of a new latent form of Plasmodium cynomolgi (the hypnozoite), and failure to detect hepatic forms within the first 24 hours after infection. Am J Trop Med Hyg 31:24–35PubMedGoogle Scholar
  30. Krotoski WA, Bray RS, Garnham PCC, Gwadz RW, Killick-Kendrick R, Draper CC, Targett GAT, Krotoski DM, Guy MW, Koontz LC, Cogswell FB (1982b) Observations on early and late post-sporozoite tissue stages in primate malaria. II. The hypnozoite of Plasmodium cynomolgi bastianellii from 3 to 105 days after infection, and detection of 36- to 40-hour pre-erythrocytic forms. Am J Trop Med Hyg 31:211–225PubMedGoogle Scholar
  31. Krotoski WA, Collins WE, Bray RS, Garnham PCC, Cogswell FB, Gwadz RW, Killick-Kendrick R, Wolf R, Sinden R, Koontz LC, Stanfill PS (1982c) Demonstration of hypnozoites in sporozoite-transmitted Plasmodium vivax infection. Am J Trop Med Hyg 31:1291–1293PubMedGoogle Scholar
  32. Krotoski WA, Garnham PCC, Cogswell FB, Collins WE, Bray RS, Gwadz RW, Killick-Kendrick R, Wolf RH, Sinden R, Hollingdale M, Lowrie RC, Koontz LC, Stanfill PS (1986) Observations on early and late post-sporozoite tissue stages in primate malaria. IV. Pre-erythrocytic schizonts and/or hypnozoites of Chesson and North Korean strains of Plasmodium vivax in the chimpanzee. Am J Trop Med Hyg 35:263–274PubMedGoogle Scholar
  33. Landau I, Chabaud AG, Mora-Silvera E, Coquelin F, Boulard Y, Rénia L, Snounou G (1999) Survival of rodent malaria merozoites in the lymphatic network: potential role in chronicity of the infection. Parasite 6:311–322PubMedGoogle Scholar
  34. Lindsay DS, Sundermann CA, Blagburn BL (1988) Caryocyst-like host cell formation by Caryospora duszynskii (Apicomplexa: Eimeriidae) in human fetal lung cell cultures. J Protozool 35:32–33PubMedGoogle Scholar
  35. Lindsay DS, Dubey JP, Blagburn BL (1997a) Biology of Isospora spp. from humans, nonhuman primates, and domestic animals. Clin Microbiol Rev 10:19–34PubMedGoogle Scholar
  36. Lindsay DS, Dubey JP, Toivio-Kinnucan MA, Michiels JF, Blagburn BL (1997b) Examination of extraintestinal tissue cysts of Isospora belli. J Parasitol 83:620–625CrossRefPubMedGoogle Scholar
  37. Liu D, Lou S, Shu H, Fu R, Ye B (1995) Effect of environmental temperature, cryopreservation and ageing on Plasmodium vivax sporozoites developing into exoerythrocytic stages [In Chinese]. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 13:165–169PubMedGoogle Scholar
  38. Lysenko AJ, Beljaev AE, Rybalka VM (1977) Population studies of Plasmodium vivax. 1. The theory of polymorphism of sporozoites and epidemiological phenomena of tertian malaria. Bull WHO 55:541–549PubMedGoogle Scholar
  39. Markus MB (1970) Studies on blood parasites of birds, with special reference to seasonal variations in parasitaemia. MSc Dissertation, London School of Hygiene and Tropical Medicine, University of LondonGoogle Scholar
  40. Markus MB (1976) Possible support for the sporozoite hypothesis of relapse and latency in malaria. Trans R Soc Trop Med Hyg 70:535CrossRefPubMedGoogle Scholar
  41. Markus MB (1977) Isospora of mammals in the intermediate host. Proc 5th Int Congr Protozool, New York, p 395Google Scholar
  42. Markus MB (1978a) Terminology for invasive stages of protozoa of the subphylum Apicomplexa (Sporozoa). S Afr J Sci 74:105–106Google Scholar
  43. Markus MB (1978b) Terminology for invasive stages of the subphylum Sporozoa (Apicomplexa). Proc IVth Int Congr Parasitol (Warsaw) B, pp 79–80Google Scholar
  44. Markus MB (1978c) Terms for invasive stages of protozoa of the subphylum Sporozoa (Apicomplexa). Parasitology 77:vii–viiiGoogle Scholar
  45. Markus MB (1980) The malarial hypnozoite. Lancet 1:936CrossRefPubMedGoogle Scholar
  46. Markus MB (1983) The hypnozoite of Isospora canis. S Afr J Sci 79:117Google Scholar
  47. Markus MB (1984) Recrudescence, recurrence and relapse in malaria. S Afr Med J 66:164PubMedGoogle Scholar
  48. Markus MB (1987) Terms for coccidian merozoites. Ann Trop Med Parasitol 81:463PubMedGoogle Scholar
  49. Markus MB (1998) Hypnozoites and malaria. Parasitol Today 14:377CrossRefPubMedGoogle Scholar
  50. Markus MB (2003) Toxoplasma gondii. In: Miliotis MD, Bier JW (eds) International handbook of foodborne pathogens. Marcel Dekker, New York, pp 511–523Google Scholar
  51. Markus MB (2004) What is the “monozoic cyst” of Isospora belli in HIV/AIDS? J Eukaryot Microbiol 51:17A–18AGoogle Scholar
  52. Markus MB (2010) Malaria: origin of the term hypnozoite. J Hist Biol. doi: 10.1007/s10739-010-9239-3 PubMedGoogle Scholar
  53. Markus MB, Van Der Lugt JJ, Dubey JP (2004) Sarcocystosis. In: Coetzer JAW, Tustin RC (eds) Infectious diseases of livestock, vol 1, 2nd edn. Oxford University Press, Cape Town, pp 360–375Google Scholar
  54. Mehlhorn H (2008) Encyclopedia of parasitology, 3rd edn. Springer, HeidelbergCrossRefGoogle Scholar
  55. Mehlhorn H, Markus MB (1976) Electron microscopy of stages of Isospora felis of the cat in the mesenteric lymph node of the mouse. Z Parasitenkd 51:15–24CrossRefPubMedGoogle Scholar
  56. Millet P, Anderson P, Collins WE (1994) In vitro cultivation of exoerythrocytic stages of the simian malaria parasites Plasmodium fieldi and Plasmodium simiovale in rhesus monkey hepatocytes. J Parasitol 80:384–388CrossRefPubMedGoogle Scholar
  57. Muehlenbachs A, Mutabingwa TK, Fried M, Duffy PE (2007) An unusual presentation of placental malaria: a single persisting nidus of sequestered parasites. Human Pathol 38:520–523CrossRefGoogle Scholar
  58. Orjuela-Sánchez P, da Silva NS, da Silva-Nunes M, Ferreira MU (2009) Recurrent parasitemias and population dynamics of Plasmodium vivax polymorphisms in rural Amazonia. Am J Trop Med Hyg 81:961–968CrossRefPubMedGoogle Scholar
  59. Poilane I, Jeantils V, Carbillon L (2009) Découverte fortuite de paludisme à Plasmodium falciparum au cours de la grossesse : à propos de deux cas. Gynécol Obstét Fertil 37:824–826CrossRefPubMedGoogle Scholar
  60. Rankin KE, Graewe S, Heussler VT, Stanway RR (2010) Imaging liver-stage malaria parasites. Cell Microbiol 12:569–579CrossRefPubMedGoogle Scholar
  61. Shortt HE, Garnham PCC (1948) Demonstration of a persisting exo-erythrocytic cycle in Plasmodium cynomolgi and its bearing on the production of relapses. Brit Med J 1:1225–1228CrossRefPubMedGoogle Scholar
  62. Shu H, Lou S, Liu D, Fu R (1995) Observations on hypnozoites of different isolates of Plasmodium vivax in cultured materials [In Chinese]. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 13:185–188PubMedGoogle Scholar
  63. Shute PG (1946) Latency and long-term relapses in benign tertian malaria. Trans R Soc Trop Med Hyg 40:189–200CrossRefPubMedGoogle Scholar
  64. Shute PG, Lupascu G, Branzei P, Maryon M, Constantinescu P, Bruce-Chwatt LJ, Draper CC, Killick-Kendrick R, Garnham PCC (1976) A strain of Plasmodium vivax characterized by prolonged incubation: the effect of numbers of sporozoites on the length of the prepatent period. Trans R Soc Trop Med Hyg 70:474–481CrossRefPubMedGoogle Scholar
  65. Speer CA, Reduker DW, Burgess DE, Whitmire WM, Splitter GA (1985) Lymphokine-induced inhibition of growth of Eimeria bovis and Eimeria papillata (Apicomplexa) in cultured bovine monocytes. Infect Immun 50:566–571PubMedGoogle Scholar
  66. Stanway RR, Graewe S, Rennenberg A, Helm S, Heussler VT (2009) Highly efficient subcloning of rodent malaria parasites by injection of single merosomes or detached cells. Nat Protoc 4:1433–1439CrossRefPubMedGoogle Scholar
  67. Sturm A, Amino R, van de Sand C, Regen T, Retzlaff S, Rennenberg A, Krueger A, Pollok J, Ménard R, Heussler VT (2006) Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids. Science 313:1287–1290CrossRefPubMedGoogle Scholar
  68. Sundermann CA, Lindsay DS (1989) Ultrastructure of in vivo-produced caryocysts containing the coccidian Caryospora bigenetica (Apicomplexa: Eimeriidae). J Protozool 36:81–86PubMedGoogle Scholar
  69. Sutherland CJ, Tanomsing N, Nolder D, Oguike M, Jennison C, Pukrittayakamee S, Dolecek C, Hien TT, do Rosário VE, Arez AP, Pinto J, Michon P, Escalante AA, Nosten F, Burke M, Lee R, Blaze M, Otto TD, Barnwell JW, Pain A, Williams J, White NJ, Day NPJ, Snounou G, Lockhart PJ, Chiodini PL, Imwong M, Polley SD (2010) Two nonrecombining sympatric forms of the human malaria parasite Plasmodium ovale occur globally. J Infect Dis 201:1544–1550CrossRefPubMedGoogle Scholar
  70. Szmitko PE, Kohn ML, Simor AE (2009) Plasmodium falciparum malaria occurring 8 years after leaving an endemic area. Diagn Microbiol Infect Dis 63:105–107CrossRefPubMedGoogle Scholar
  71. Telford SR (1989) Discovery of the pre-erythrocytic stages of a saurian malaria parasite, hypnozoites, and a possible mechanism for the maintenance of chronic infections throughout the life of the host. Int J Parasitol 19:597–616CrossRefPubMedGoogle Scholar
  72. Telford SR (1998) The development and persistence of phanerozoites in experimental infections of Plasmodium sasai. Int J Parasitol 28:475–484CrossRefPubMedGoogle Scholar
  73. Telford SR, Stein J (2000) Two malaria parasites (Apicomplexa: Plasmodiidae) of the Australian skink Egernia stokesii. J Parasitol 86:395–406PubMedGoogle Scholar
  74. Theunissen C, Janssens P, Demulder A, Nouboussié D, Van Esbroeck M, Van Gompel A, Van den Ende J (2009) Falciparum malaria in patient 9 years after leaving malaria-endemic area. Emerg Infect Dis 15:115–116CrossRefPubMedGoogle Scholar
  75. Tse B, Barta JR, Desser SS (1986) Comparative ultrastructural features of the sporozoite of Lankesterella minima (Apicomplexa) in its anuran host and leech vector. Canadian J Zool 64:2344–2347Google Scholar
  76. Valkiūnas G (2005) Avian malaria parasites and other Haemosporidia. CRC Press, Boca RatonGoogle Scholar
  77. Wells TNC, Burrows JN, Baird JK (2010) Targeting the hypnozoite reservoir of Plasmodium vivax: the hidden obstacle to malaria elimination. Trends Parasitol 26:145–151CrossRefPubMedGoogle Scholar
  78. Westenberger SJ, McClean CM, Chattopadhyay R, Dharia NV, Carlton JM, Barnwell JW, Collins WE, Hoffman SL, Zhou Y, Vinetz JM, Winzeler EA (2010) A systems-based analysis of Plasmodium vivax lifecycle transcription from human to mosquito. PLoS Negl Trop Dis 4(4):e653CrossRefPubMedGoogle Scholar
  79. World Health Organization (2010) Guidelines for the treatment of malaria. WHO, GenevaGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Imperial College LondonLondonUK
  2. 2.School of Animal, Plant and Environmental SciencesUniversity of WitwatersrandJohannesburgSouth Africa

Personalised recommendations